ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6125A>G (p.Gln2042Arg) (rs80358852)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160108 SCV000210383 uncertain significance not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6125A>G at the cDNA level, p.Gln2042Arg (Q2042R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). Using alternate nomenclature, this variant would be defined as BRCA2 6353A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln2042Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Gln2042Arg is located in the RAD51 binding domain (Roy 2012). 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 Gln2042Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200820 SCV000254199 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-01 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 2042 of the BRCA2 protein (p.Gln2042Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs80358852, ExAC 0.03%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 38019). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000219164 SCV000276482 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000031600 SCV000784909 uncertain significance Breast-ovarian cancer, familial 2 2017-02-07 criteria provided, single submitter clinical testing
Color RCV000219164 SCV000911401 likely benign Hereditary cancer-predisposing syndrome 2017-06-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779953 SCV000916909 uncertain significance not specified 2019-07-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6125A>G (p.Gln2042Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 282338 control chromosomes, predominantly at a frequency of 0.00036 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6125A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. The variant has been reported in the FLOSSIES database in 3 women older than age 70 years who have never had cancer, providing supporting evidence for a benign role. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x) and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharing Clinical Reports Project (SCRP) RCV000031600 SCV000054207 uncertain significance Breast-ovarian cancer, familial 2 2010-02-20 no assertion criteria provided clinical testing

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