ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8141A>G (p.Gln2714Arg) (rs80359059)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045430 SCV000073443 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 2714 of the BRCA2 protein (p.Gln2714Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 17413421). This variant is also known as 8369A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 52512). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the BRCA2 gene (PMID: 19043619), suggest that this missense change is likely to be tolerated. The arginine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000129843 SCV000184660 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000212270 SCV000210463 uncertain significance not provided 2017-09-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8141A>G at the cDNA level, p.Gln2714Arg (Q2714R) 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/ has been previously published as BRCA2 8369A>G. This variant has been observed in an individual with epithelial ovarian cancer (Jacobi 2007). BRCA2 Gln2714Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln2714Arg occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Gln2714Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000113876 SCV000785601 uncertain significance Breast-ovarian cancer, familial 2 2017-10-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781082 SCV000918893 uncertain significance not specified 2018-04-02 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8141A>G (p.Gln2714Arg) results in a conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246112 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.8141A>G has been reported in the literature in individuals affected with Ovarian Cancer (Jacobi_2007). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113876 SCV000147281 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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