ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130809 SCV000185705 likely benign Hereditary cancer-predisposing syndrome 2020-01-25 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Structural 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 Health, Inc RCV000130809 SCV000689111 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-07 criteria provided, single submitter clinical testing
Invitae RCV000637597 SCV000759063 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-06-03 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 individual(s) 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 C1). 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. 5
Counsyl RCV000031734 SCV000785174 uncertain significance Breast-ovarian cancer, familial 2 2017-05-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000218650 SCV001133928 uncertain significance not provided 2019-02-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192649 SCV001360904 uncertain significance not specified 2019-10-03 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8309C>A (p.Ala2770Asp) results in a non-conservative amino acid change located in the OB1 (oligonucleotide binding) fold (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248382 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, there are no reports of c.8309C>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating an impact on protein function in the literature. The variant has been detected as a somatic mutation in an individual with cervical carcinoma (Muller_2015). Five ClinVar submissions (evaluation after 2014) have cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
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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