ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4850G>A (p.Ser1617Asn) (rs397507341)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166443 SCV000217238 likely benign Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV001703438 SCV000520481 likely benign not provided 2018-04-05 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21232165, 21120943)
Invitae RCV000697920 SCV000826554 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-03-11 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1617 of the BRCA2 protein (p.Ser1617Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs397507341, ExAC 0.002%). This variant has been reported in families affected with breast and/or ovarian cancer (PMID: 21232165). ClinVar contains an entry for this variant (Variation ID: 37928). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000697920 SCV000890913 uncertain significance Hereditary breast and ovarian cancer syndrome 2021-08-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166443 SCV000906092 likely benign Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000437440 SCV001442544 uncertain significance not specified 2020-10-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4850G>A (p.Ser1617Asn) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250024 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4850G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Stegel_2011). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA2 c.3599_3600delGT, p.Cys1200X; UMD), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and three ClinVar submitters (evaluation after 2014) cite it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharing Clinical Reports Project (SCRP) RCV000031509 SCV000054114 likely benign Breast-ovarian cancer, familial 2 2010-10-04 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000437440 SCV000587727 uncertain significance not specified 2014-01-31 no assertion criteria provided research

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