ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3128G>C (p.Gly1043Ala)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024675.4(PALB2):c.3128G>C (p.Gly1043Ala)
Variation ID: 126716 Accession: VCV000126716.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23614077 (GRCh38) [ NCBI UCSC ] 16: 23625398 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 19, 2014 May 1, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.3128G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Gly1043Ala missense NC_000016.10:g.23614077C>G NC_000016.9:g.23625398C>G NG_007406.1:g.32281G>C LRG_308:g.32281G>C LRG_308t1:c.3128G>C LRG_308p1:p.Gly1043Ala Q86YC2:p.Gly1043Ala - Protein change
- G1043A
- Other names
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- Canonical SPDI
- NC_000016.10:23614076:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PALB2 | - | - |
GRCh38 GRCh37 |
5836 | 5875 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000114598.16 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jun 9, 2023 | RCV000131630.17 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jun 23, 2023 | RCV000485289.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 20, 2021 | RCV000780560.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 22, 2022 | RCV002483180.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Oct 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201990.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jan 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000550620.10
First in ClinVar: May 11, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1043 of the PALB2 protein (p.Gly1043Ala). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1043 of the PALB2 protein (p.Gly1043Ala). This variant is present in population databases (rs377713277, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 21365267, 21618343, 26283626, 26315354, 26564480). ClinVar contains an entry for this variant (Variation ID: 126716). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 31586400, 31636395). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jun 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000186653.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.G1043A variant (also known as c.3128G>C), located in coding exon 11 of the PALB2 gene, results from a G to C substitution at nucleotide … (more)
The p.G1043A variant (also known as c.3128G>C), located in coding exon 11 of the PALB2 gene, results from a G to C substitution at nucleotide position 3128. The glycine at codon 1043 is replaced by alanine, an amino acid with similar properties. This variant is located in the carboxy-terminal WD40-repeat motif of the PALB2 protein, near the region where BRCA2 binds across a hydrophobic pocket of PALB2 (codons 1053–1057) (Oliver AW et al. EMBO Rep. 2009 Sep; 10(9):990-6; Hofstatter EW et al. Fam Cancer. 2011 Jun; 10(2):225-31). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med. 2020 Mar;22:622-632). Whereas another group performed multiple functional studies and demonstrated that this alteration leads to intermediate functional defects; specifically, this alteration was found to have an intermediate recombination defect with reduced HDR activity of 50% compared to the wildtype control, despite normal nuclear localization and modest decrease of RAD51 foci (Rodrigue A et al. Nucleic Acids Res. 2019 11;47:10662-10677). This alteration has been reported in multiple cohorts of patients with a personal and/or family history of breast and/or ovarian cancer; however, this alteration was also identified in healthy controls (Hofstatter EW et al. Fam Cancer. 2011 Jun; 10(2):225-31; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Damiola F et al. Breast Cancer Res. Treat. 2015 Dec;154(3):463-71; Kanchi KL et al. Nat Commun. 2014;5:3156; Dorling et al. N Engl J Med, 2021 02;384:428-439; Lerner-Ellis J et al. J Cancer Res Clin Oncol 2021 Mar;147(3):871-879; Gonzalez A et al, Breast Cancer Res Treat 2022 Jul;194(2):403-412). This variant did not co-segregate with disease in one breast cancer family reported in published literature; this family had two sisters affected with breast cancer and only one carried the variant (Hellebrand H et al. 2011. Hum Mutat. 2011 Jun;32(6):E2176-88). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jul 30, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Accession: SCV001424031.1
First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020 |
Comment:
This sequence variant is a single nucleotide substitution (G>C) that results in a glycine to alanine amino acid change at residue 1043 in the PALB2 … (more)
This sequence variant is a single nucleotide substitution (G>C) that results in a glycine to alanine amino acid change at residue 1043 in the PALB2 protein. This is a previously reported (ClinVar, HGMD), rare variant in control population datasets (gnomAD database, 5/245648 alleles, 0.002% overall frequency) that has also been observed in multiple breast and ovarian cancer patients (PMIDs 21365267, 21618343, 26283626, 26315354). The Gly1043 residue is located within the functional domain of PALB2 necessary for its interaction with BRCA2 (PMIDs 24485656, 17200672), but functional studies have not been performed to determine if this interaction is disrupted in the presence of this variant. Multiple bioinformatic tools queried are in agreement that this amino acid change would be damaging, and the Gly1043 residue is completely evolutionarily conserved across more than 50 mammalian species examined. At this time, there is not enough evidence to determine whether this variant is pathogenic or benign; thus, it is a variant of uncertain significance. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Aug 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917938.2
First in ClinVar: Jun 02, 2019 Last updated: Sep 08, 2021 |
Comment:
Variant summary: PALB2 c.3128G>C (p.Gly1043Ala) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the … (more)
Variant summary: PALB2 c.3128G>C (p.Gly1043Ala) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 263364 control chromosomes. c.3128G>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (examples- Hellebrand_2011, Hofstatter_2011, Tung_2014, Ramus_2015, Thompson_2015), but also in controls (examples- Kanchi_2014, Damiola_2015, Girard_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several publications report experimental evidence evaluating an impact on protein function, reporting conflicting results. In one study, the variant was reported to have no significant effect on homology-directed repair (HDR) activity (Wiltshire_2019), but in another study modest reductions in HDR activity were observed, and the variant protein was shown to exhibit reduced interaction with BRCA2 in a mammalian two hybrid assay (Rodrigue_2019). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 14, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002530756.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PALB2 c.3128G>C (p.G1043A) variant has been reported individuals with breast and/or ovarian cancer (PMID: 21365267, 21618343, 25186627, 26283626, 26315354). However, it was also reported … (more)
The PALB2 c.3128G>C (p.G1043A) variant has been reported individuals with breast and/or ovarian cancer (PMID: 21365267, 21618343, 25186627, 26283626, 26315354). However, it was also reported in controls (PMID: 24448499, 26564480). Additionally, in at least one family the variant did not segregate with the disease (PMID: 21618343). Functional studies demonstrated normal or partially impaired function of the protein (PMID: 31586400, 31636395). This variant was observed in 4/113426 chromosomes in the Non-Finnish European population, with no homozygotes, according to the Genome Aggregation Database (PMID: 32461654). There is no indication that this variant causes disease, but the evidence is insufficient currently to prove that conclusively. Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)
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Uncertain significance
(Jun 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000566840.7
First in ClinVar: Apr 29, 2017 Last updated: Jul 01, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26564480, 26315354, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26564480, 26315354, 21365267, 21618343, 25186627, 26283626, 31586400, 31636395, 33195396, 33471991, 30303537, 31422574, 24448499) (less)
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Uncertain significance
(Jun 01, 2015)
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criteria provided, single submitter
Method: case-control
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Familial cancer of breast
Cases recruited through familial
(more...)
Affected status: yes
Allele origin:
germline
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Cancer Genetics Laboratory, Peter MacCallum Cancer Centre
Accession: SCV000268023.1
First in ClinVar: May 11, 2016 Last updated: May 11, 2016 |
Number of individuals with the variant: 1
Sex: female
Geographic origin: Australia
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Uncertain significance
(Apr 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002788182.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(May 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000537611.6
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with alanine at codon 1043 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glycine with alanine at codon 1043 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant has partially reduced to near full PALB2 activities compared to wild-type in homology-directed repair assays (PMID: 31636395, 31586400), and partial loss-of-function in subcellular localization and PARP inhibitor sensitivity assays (PMID: 31586400). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 21365267, 21618343, 25186627, 26283626, 26315354). This variant has also been reported in breast and ovarian cancer case-control studies in unaffected individuals but absent in cases (PMID: 26564480, 30303537, 33471991; Leiden Open Variation Database DB-ID PALB2_010151). This variant has been identified in 4/250794 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550164.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
PALB2, EXON11, c.3128G>C, p.Gly1043Ala, Heterozygous, Uncertain Significance The PALB2 p.Gly1043Ala variant was identified in 5 of 16464 proband chromosomes (frequency: 0.0003) from individuals or families … (more)
PALB2, EXON11, c.3128G>C, p.Gly1043Ala, Heterozygous, Uncertain Significance The PALB2 p.Gly1043Ala variant was identified in 5 of 16464 proband chromosomes (frequency: 0.0003) from individuals or families with breast and ovarian cancer and was present in 1 of 1324 control chromosomes (frequency: 0.0008) from healthy individuals (Damiola 2015, Hellebrand 2011, Hofstatter 2011, Ramus 2015, Thompson 2015, Tung 2015). The variant was also identified in the following databases: dbSNP (ID: rs377713277) as "With Uncertain significance allele", ClinVar (6x uncertain significance), Clinvitae, and LOVD 3.0 (4x). The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 5 of 245648 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the European population in 5 of 111408 chromosomes (freq: 0.00005), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Gly1043 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the c.3128G>C variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
Number of individuals with the variant: 1
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Uncertain significance
(May 13, 2019)
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no assertion criteria provided
Method: curation
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001193358.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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PALB2 germline mutations in a multi-gene panel testing cohort of 1905 breast-ovarian cancer patients in Argentina. | Gonzalez A | Breast cancer research and treatment | 2022 | PMID: 35610400 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Functional characterization of 84 PALB2 variants of uncertain significance. | Wiltshire T | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31636395 |
A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor. | Rodrigue A | Nucleic acids research | 2019 | PMID: 31586400 |
Prevalence of genetic susceptibility for breast and ovarian cancer in a non-cancer related study population: secondary germline findings from a Swiss single centre cohort. | Kraemer D | Swiss medical weekly | 2019 | PMID: 31422574 |
Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. | Girard E | International journal of cancer | 2019 | PMID: 30303537 |
Mutation analysis of PALB2 gene in French breast cancer families. | Damiola F | Breast cancer research and treatment | 2015 | PMID: 26564480 |
Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. | Ramus SJ | Journal of the National Cancer Institute | 2015 | PMID: 26315354 |
Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls. | Thompson ER | Breast cancer research : BCR | 2015 | PMID: 26283626 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Breast cancer proteins PALB2 and BRCA2 stimulate polymerase η in recombination-associated DNA synthesis at blocked replication forks. | Buisson R | Cell reports | 2014 | PMID: 24485656 |
Integrated analysis of germline and somatic variants in ovarian cancer. | Kanchi KL | Nature communications | 2014 | PMID: 24448499 |
Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. | Hellebrand H | Human mutation | 2011 | PMID: 21618343 |
PALB2 mutations in familial breast and pancreatic cancer. | Hofstatter EW | Familial cancer | 2011 | PMID: 21365267 |
Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. | Xia B | Nature genetics | 2007 | PMID: 17200672 |
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Text-mined citations for rs377713277 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.