ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6916G>T (p.Ala2306Ser) (rs730881550)

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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 RCV000165458 SCV000216188 uncertain significance Hereditary cancer-predisposing syndrome 2014-09-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000160122 SCV000210406 uncertain significance not provided 2018-09-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6916G>T at the cDNA level, p.Ala2306Ser (A2306S) at the protein level, and results in the change of an Alanine to a Serine (GCT>TCT). Using alternate nomenclature, this variant would be defined as 7144G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2306Ser was not 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 Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala2306Ser occurs at a position that is not conserved and is not located in a known functional domain (Cole 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ala2306Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000543240 SCV000635544 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 2306 of the BRCA2 protein (p.Ala2306Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. 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: 182234). 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 C25". The serine 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.

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