ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10160C>G (p.Thr3387Ser) (rs863224584)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197203 SCV000254166 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-06-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 3387 of the BRCA2 protein (p.Thr3387Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with breast cancer (Invitae). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that this c.10160C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 216239). 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 serine 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.
Ambry Genetics RCV000222578 SCV000275484 likely benign Hereditary cancer-predisposing syndrome 2019-04-11 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000613680 SCV000694498 uncertain significance not specified 2020-11-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.10160C>G (p.Thr3387Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251190 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.10160C>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=3). At-least two submitters report this variant as having co-occurred with another pathogenic variant in the BRCA2 gene, however, the exact co-occurring variant is not specified. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV000613680 SCV000725488 likely benign not specified 2017-11-29 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000662771 SCV000785572 uncertain significance Breast-ovarian cancer, familial 2 2017-10-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000222578 SCV000906832 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-03 criteria provided, single submitter clinical testing

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