ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.695A>G (p.Tyr232Cys) (rs372188754)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129831 SCV000184647 likely benign Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Color RCV000129831 SCV000911097 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656999 SCV000232905 uncertain significance not provided 2015-04-16 criteria provided, single submitter clinical testing
GeneDx RCV000656999 SCV000565866 uncertain significance not provided 2017-06-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.695A>G at the cDNA level, p.Tyr232Cys (Y232C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 923A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Tyr232Cys was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr232Cys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Tyr232Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200246 SCV000254202 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 232 of the BRCA2 protein (p.Tyr232Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs372188754, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 141345). 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 cysteine 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000239053 SCV000296750 uncertain significance Breast-ovarian cancer, familial 2 2016-04-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656999 SCV000889117 uncertain significance not provided 2018-05-21 criteria provided, single submitter clinical testing

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