ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8309C>A (p.Ala2770Asp) (rs28897750)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130809 SCV000185705 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000218650 SCV000279828 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8309C>A at the cDNA level, p.Ala2770Asp (A2770D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCC>GAC). Using alternate nomenclature, this variant would be defined as BRCA2 8537C>A. This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a cervical tumor (Muller 2015). BRCA2 Ala2770Asp was not observed in large population cohorts (Lek 2016). Since Alanine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala2770Asp is located in the DNA binding domain (Yang 2002). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ala2770Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130809 SCV000689111 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
Invitae RCV000637597 SCV000759063 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 2770 of the BRCA2 protein (p.Ala2770Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a individual affected with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 38151). 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, 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.
Counsyl RCV000031734 SCV000785174 uncertain significance Breast-ovarian cancer, familial 2 2017-05-26 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031734 SCV000054341 uncertain significance Breast-ovarian cancer, familial 2 2009-04-22 no assertion criteria provided clinical testing

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