ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4894_4895del (p.Ser1632fs) (rs397507748)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000257591 SCV000324281 pathogenic Breast-ovarian cancer, familial 2 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000257591 SCV000327101 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781113 SCV000918952 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-31 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4894_4895delAG (p.Ser1632TyrfsX6) 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 (e.g. p.Glu1646fsX23, p.Tyr1655X and p.Val1681fsX7). The variant was absent in 119866 control chromosomes (ExAC and publication data). c.4894_4895delAG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Seong 2009, Kim 2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000781113 SCV001578001 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser1632Tyrfs*6) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with BRCA2-related conditions (PMID: 19656164, 22798144). ClinVar contains an entry for this variant (Variation ID: 51735). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

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