ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3242G>A (p.Cys1081Tyr) (rs752871893)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482401 SCV000566361 uncertain significance not provided 2015-04-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3242G>A at the cDNA level, p.Cys1081Tyr (C1081Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). Using alternate nomenclature, this variant would be defined as BRCA2 3470G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Cys1081Tyr 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 Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Cys1081Tyr occurs at a position that is not conserved across species and is not located within a known functional domain but is located within a region responsible for interaction with RAD51 (Roy 2012, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Cys1081Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000579848 SCV000683539 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-03 criteria provided, single submitter clinical testing
Invitae RCV000812619 SCV000952938 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1081 of the BRCA2 protein (p.Cys1081Tyr). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 418936). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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