ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.229del (p.Cys77fs)
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.229del (p.Cys77fs)
Variation ID: 126644 Accession: VCV000126644.26
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23636317 (GRCh38) [ NCBI UCSC ] 16: 23647638 (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 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.229del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Cys77fs frameshift NM_024675.4:c.229delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_024675.3:c.229delT NC_000016.10:g.23636317del NC_000016.9:g.23647638del NG_007406.1:g.10041del LRG_308:g.10041del LRG_308t1:c.229del LRG_308p1:p.Cys77fs - Protein change
- C77fs
- Other names
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- Canonical SPDI
- NC_000016.10:23636316:A:
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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
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 6, 2023 | RCV000114519.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 8, 2023 | RCV000236050.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000772121.7 | |
Pathogenic (1) |
criteria provided, single submitter
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May 25, 2020 | RCV001798297.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2021 | RCV002267609.2 |
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
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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
Help
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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Pathogenic
(May 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002043592.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
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Pathogenic
(Sep 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134542.3
First in ClinVar: Jan 04, 2020 Last updated: Jan 01, 2022 |
Comment:
The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one … (more)
The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
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Pathogenic
(Oct 07, 2021)
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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: SCV004202777.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Aug 29, 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:
germline
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Invitae
Accession: SCV000260770.6
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys77Valfs*100) in the PALB2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Cys77Valfs*100) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs180177084, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 17420451, 23341105). ClinVar contains an entry for this variant (Variation ID: 126644). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 29, 2024)
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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: SCV002733976.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.229delT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 229, causing … (more)
The c.229delT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 229, causing a translational frameshift with a predicted alternate stop codon (p.C77Vfs*100). This mutation has been seen in multiple breast cancer families and was demonstrated to result in a protein product with reduced binding to BRCA2 and deficient homologous recombination (Antoniou AC et al. N. Engl. J. Med., 2014 Aug;371:497-506; Tischkowitz M et al. Proc. Natl. Acad. Sci. U.S.A., 2007 Apr;104:6788-93). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Oct 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002549767.2
First in ClinVar: Jul 23, 2022 Last updated: Dec 17, 2022 |
Comment:
PALB2:c.229del is a deletion of a single nucleotide in exon 4 predicted to encode a frameshift of the mature mRNA with consequent premature termination of … (more)
PALB2:c.229del is a deletion of a single nucleotide in exon 4 predicted to encode a frameshift of the mature mRNA with consequent premature termination of protein synthesis at codon 100 of the frameshift, or 176 (PALB2:p.(Cys77ValfsTer100)) using NP_078951.2. This is predicted to result in absent PALB2 protein due to nonsense mediated decay (NMD). If NMD is escaped, this variant is expected to encode a truncated protein. Variants of this type are widely accepted to be pathogenic (Tayoun, et al., 2018, PMID:30192042) (PVS1). PALB2:c.229del (rs180177084) is rare in population databases (gnomAD=0.00066%) (PM2). This variant has not been reported in the scientific literature in association with colon cancer. This variant has been identified in one Scottish family with multiple recurrences of breast cancer in three individuals (Tischkowitz et al., 2007, PMID: 17420451) (PS4_Supporting). Functional studies showed that this variant produced a truncated protein that had minimal BRCA2 binding capacity and defective double strand break repair by homologous recombination (Tischkowitz et al., 2007, PMID: 17420451). This variant is on record in ClinVar (Variation ID:126644) reported by multiple clinical laboratories without conflict as pathogenic in association with hereditary cancer-predisposing syndrome and familial cancer of breast. This variant is listed in HGMD as ‘disease causing mutation’ in association with the breast cancer phenotype (Accession: CD072459). (less)
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Pathogenic
(Mar 08, 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: SCV000293388.10
First in ClinVar: Jul 24, 2016 Last updated: Jul 22, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21113654, 26790966, 23341105, 18302019, 18628482, 20346647, 19333784, 21618343, 25099575, 19264984, 20213081, 27783279, 26411315, 27535533, 17420451, 33964450) (less)
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Pathogenic
(Sep 06, 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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Myriad Genetics, Inc.
Accession: SCV004189471.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Jan 15, 2020)
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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: SCV000905195.3
First in ClinVar: May 20, 2019 Last updated: Jan 12, 2022 |
Comment:
This variant deletes 1 nucleotide in exon 4 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 4 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/31356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(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: SCV001192952.1
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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Breast-cancer risk in families with mutations in PALB2. | Antoniou AC | The New England journal of medicine | 2014 | PMID: 25099575 |
The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer. | Janatova M | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2013 | PMID: 24136930 |
Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three-dimensional nuclear organization of patient-derived cell lines. | Wark L | Genes, chromosomes & cancer | 2013 | PMID: 23341105 |
Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. | Jones S | Science (New York, N.Y.) | 2009 | PMID: 19264984 |
Analysis of PALB2/FANCN-associated breast cancer families. | Tischkowitz M | Proceedings of the National Academy of Sciences of the United States of America | 2007 | PMID: 17420451 |
Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. | Xia B | Nature genetics | 2007 | PMID: 17200672 |
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. | Reid S | Nature genetics | 2007 | PMID: 17200671 |
PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. | Rahman N | Nature genetics | 2007 | PMID: 17200668 |
Text-mined citations for rs180177084 ...
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.