ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8180C>G (p.Ala2727Gly) (rs879255468)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000469799 SCV000549522 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 2727 of the BRCA2 protein (p.Ala2727Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. 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: 252853). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV000483895 SCV000566582 uncertain significance not provided 2015-05-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8180C>G at the cDNA level, p.Ala2727Gly (A2727G) at the protein level, and results in the change of an Alanine to a Glycine (GCT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 8408C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2727Gly 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 Glycine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ala2727Gly occurs at a position that is conserved in 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 Ala2727Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000565073 SCV000661395 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-05 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000565073 SCV000905231 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000238976 SCV000297456 uncertain significance Breast-ovarian cancer, familial 2 2013-09-03 no assertion criteria provided clinical testing

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