ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.4964dup (p.Tyr1655Ter)
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_000059.4(BRCA2):c.4964dup (p.Tyr1655Ter)
Variation ID: 91830 Accession: VCV000091830.21
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32339318-32339319 (GRCh38) [ NCBI UCSC ] 13: 32913455-32913456 (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 Sep 27, 2014 Feb 28, 2024 Sep 8, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.4964dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Tyr1655Ter nonsense NM_000059.3:c.4964dupA NC_000013.11:g.32339319dup NC_000013.10:g.32913456dup NG_012772.3:g.28840dup LRG_293:g.28840dup - Protein change
- Y1655*
- Other names
- 5192insA
- Canonical SPDI
- NC_000013.11:32339318:A:AA
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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
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The frequency of the allele represented by this VCV record.
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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
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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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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18542 | 18699 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (3) |
reviewed by expert panel
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Sep 8, 2016 | RCV000077738.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 16, 2021 | RCV000218684.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 6, 2023 | RCV000480916.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 17, 2023 | RCV000557404.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 10, 2021 | RCV003474670.1 |
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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Pathogenic
(Sep 08, 2016)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000300807.2
First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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Pathogenic
(Jun 16, 2021)
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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: SCV000273734.6
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The c.4964dupA pathogenic mutation (also known as p.Y1655*), located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide … (more)
The c.4964dupA pathogenic mutation (also known as p.Y1655*), located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 4964. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This mutation was identified in individuals of Portuguese ancestry, including two with high grade serous ovarian cancer (Peixoto A et al. Clin Genet, 2015 Jul;88:41-8; Peixoto A et al. Front Oncol, 2020 Jul;10:1318). This mutation was reported in 3 of 649 Brazilian probands with HBOC (Palmero EI et al. Sci Rep, 2018 06;8:9188). 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)
Number of individuals with the variant: 1
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Pathogenic
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000327113.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Nov 10, 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: SCV004212882.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Apr 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296733.3
First in ClinVar: Sep 27, 2014 Last updated: Jan 06, 2024 |
Comment:
This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this … (more)
This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.0000066 (1/152220 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals and/or families with hereditary breast and/or ovarian cancer (PMID: 24916970 (2015), 29907814 (2018)), and in individuals with high grade serous ovarian cancer (PMID: 32850417 (2020)). In a large breast cancer association study, this variant was reported in an individual with breast cancer (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA2). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Aug 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000635415.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91830). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91830). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and/or prostate cancer (PMID: 17688236, 20858050, 21709188, 23569316, 24728189, 24916970, 26681312). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr1655*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). (less)
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Pathogenic
(Mar 30, 2016)
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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: SCV000568470.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
This duplication of one nucleotide is denoted BRCA2 c.4964dupA at the cDNA level and p.Tyr1655Ter (Y1655X) at the protein level. The normal sequence, with the … (more)
This duplication of one nucleotide is denoted BRCA2 c.4964dupA at the cDNA level and p.Tyr1655Ter (Y1655X) at the protein level. The normal sequence, with the base that is duplicated in braces, is TGTT[A]CACA. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4964dupA, also denoted BRCA2 5192dupA using alternate nomenclature, has been reported in association with hereditary breast /ovarian cancer (Peixoto 2014). This variant is considered pathogenic. (less)
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Pathogenic
(May 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360792.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: BRCA2 c.4964dupA (p.Tyr1655X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BRCA2 c.4964dupA (p.Tyr1655X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 240078 control chromosomes. c.4964dupA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Peixoto_2014; Palmero_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 01, 2009)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000109541.2
First in ClinVar: Dec 23, 2013 Last updated: Sep 27, 2014 |
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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 Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Tumor Testing for Somatic and Germline BRCA1/BRCA2 Variants in Ovarian Cancer Patients in the Context of Strong Founder Effects. | Peixoto A | Frontiers in oncology | 2020 | PMID: 32850417 |
Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank. | Abul-Husn NS | Genome medicine | 2019 | PMID: 31892343 |
The germline mutational landscape of BRCA1 and BRCA2 in Brazil. | Palmero EI | Scientific reports | 2018 | PMID: 29907814 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
The role of targeted BRCA1/BRCA2 mutation analysis in hereditary breast/ovarian cancer families of Portuguese ancestry. | Peixoto A | Clinical genetics | 2015 | PMID: 24916970 |
The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. | Song H | Human molecular genetics | 2014 | PMID: 24728189 |
Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. | Castro E | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2013 | PMID: 23569316 |
Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. | Norquist B | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21709188 |
A one-step prescreening for point mutations and large rearrangement in BRCA1 and BRCA2 genes using quantitative polymerase chain reaction and high-resolution melting curve analysis. | Coulet F | Genetic testing and molecular biomarkers | 2010 | PMID: 20858050 |
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. | Borg A | Human mutation | 2010 | PMID: 20104584 |
Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. | Ramus SJ | Human mutation | 2007 | PMID: 17688236 |
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Text-mined citations for rs398122789 ...
HelpRecord last updated Apr 20, 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.