ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7547C>G (p.Ser2516Cys) (rs571800995)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220347 SCV000277527 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000215461 SCV000279529 uncertain significance not provided 2015-10-26 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7547C>G at the cDNA level and p.Ser2516Cys (S2516C) at the protein level, and results in the change of a Serine to a Cysteine (TCC>TGC). Using alternate nomenclature, this variant would be defined as BRCA2 7775C>G. This variant has not, to our knowledge, been published in the literature as either pathogenic or benign. This variant has not been observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser2516Cys occurs at a position that is conserved across species and is located within 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 Ser2516Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000467439 SCV000549555 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-12-11 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 2516 of the BRCA2 protein (p.Ser2516Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine 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: 233196). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.

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