ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1427C>G (p.Ser476Cys) (rs80358431)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132255 SCV000187338 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000031320 SCV000145871 uncertain significance Breast-ovarian cancer, familial 2 2001-02-16 no assertion criteria provided clinical testing
Color RCV000132255 SCV000903873 likely benign Hereditary cancer-predisposing syndrome 2016-04-21 criteria provided, single submitter clinical testing
Counsyl RCV000031320 SCV000488427 uncertain significance Breast-ovarian cancer, familial 2 2016-03-25 criteria provided, single submitter clinical testing
GeneDx RCV000589266 SCV000210270 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1427C>G at the cDNA level, p.Ser476Cys (S476C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 1655C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser476Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Ser476Cys is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ser476Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589266 SCV000694537 uncertain significance not provided 2016-09-02 criteria provided, single submitter clinical testing Variant summary: The c.1427C>G (p.Ser476Cys) in BRCA2 gene is a missense change that involves a conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant is absent from the control population dataset of ExAC and has not, to our knowledge, been reported in HBOC individuals via published reports. It has been reported as VUS by several reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was classified as VUS.
Invitae RCV000203653 SCV000071818 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 476 of the BRCA2 protein (p.Ser476Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). It has also been observed in an individual affected with acute myeloid leukemia (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 37739). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031320 SCV000296499 uncertain significance Breast-ovarian cancer, familial 2 2016-06-03 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031320 SCV000053925 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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