ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1826A>G (p.Gln609Arg) (rs80358473)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043904 SCV000071917 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 609 of the BRCA2 protein (p.Gln609Arg). 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 not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 51210). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is 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 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 RCV000164841 SCV000215524 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000587069 SCV000279354 uncertain significance not provided 2018-06-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1826A>G at the cDNA level, p.Gln609Arg (Q609R) 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 2054A>G. This variant was observed in at least one individual with triple negative breast cancer (Wong-Brown 2015). BRCA2 Gln609Arg was not observed in large population cohorts (Lek 2016). BRCA2 Gln609Arg and is not located in a known functional domain. 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 Gln609Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000164841 SCV000688728 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855633 SCV000694573 uncertain significance not specified 2019-02-08 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1826A>G (p.Gln609Arg) 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 was absent in 235006 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1826A>G has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Wong-Brown_2015). This report does not provide an unequivocal conclusion 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. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000083089 SCV000786093 uncertain significance Breast-ovarian cancer, familial 2 2018-02-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083089 SCV000115163 uncertain significance Breast-ovarian cancer, familial 2 2010-06-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083089 SCV000145961 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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