ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8179G>T (p.Ala2727Ser) (rs730881582)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160192 SCV000210537 uncertain significance not provided 2014-09-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8179G>T at the cDNA level, p.Ala2727Ser (A2727S) at the protein level, and results in the change of an Alanine to a Serine (GCT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2727Ser 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 Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala2727Ser occurs at a position that is conserved among mammals and is located in the DNA binding domain (Borg 2010). 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 Ala2727Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000232095 SCV000283334 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 2727 of the BRCA2 protein (p.Ala2727Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182274). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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