ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3620A>G (p.Tyr1207Cys) (rs397507310)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000218950 SCV000279490 uncertain significance not provided 2015-10-09 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3620A>G at the cDNA level, p.Tyr1207Cys (Y1207C) 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 3848A>G. This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. BRCA2 Tyr1207Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr1207Cys occurs at a position that is not conserved and is not located in a known functional domain (UniProt). 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 Tyr1207Cys is pathogenic or benign.
Invitae RCV000557673 SCV000635294 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-05-22 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1207 of the BRCA2 protein (p.Tyr1207Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 37848). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000569223 SCV000665969 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Sharing Clinical Reports Project (SCRP) RCV000031429 SCV000054034 uncertain significance Breast-ovarian cancer, familial 2 2009-02-05 no assertion criteria provided clinical testing

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