ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8714A>G (p.Tyr2905Cys) (rs431825368)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460625 SCV000549554 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-09-09 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 2905 of the BRCA2 protein (p.Tyr2905Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs431825368, ExAC 0.02%) but has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 96871). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on 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.
GeneDx RCV000479199 SCV000566552 uncertain significance not provided 2015-05-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8714A>G at the cDNA level, p.Tyr2905Cys (Y2905C) 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 8942A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Tyr2905Cys 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 Tyr2905Cys occurs at a position that is conserved across species and is located in the DNA binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Tyr2905Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000584302 SCV000689147 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000584302 SCV001179422 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-02 criteria provided, single submitter clinical testing Insufficient evidence
Sharing Clinical Reports Project (SCRP) RCV000082992 SCV000115066 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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