ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6475C>G (p.Gln2159Glu) (rs398122558)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588031 SCV000210390 uncertain significance not provided 2020-07-10 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 6703C>G; Observed in individuals with a personal or family history including breast cancer (Diaz-Zabala 2018); This variant is associated with the following publications: (PMID: 24793135, 30400234)
Ambry Genetics RCV000166819 SCV000217633 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-30 criteria provided, single submitter clinical testing The p.Q2159E variant (also known as c.6475C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 6475. The glutamine at codon 2159 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001083727 SCV000254200 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000076967 SCV000488282 uncertain significance Breast-ovarian cancer, familial 2 2016-02-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000160111 SCV000694977 likely benign not specified 2021-08-27 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6475C>G (p.Gln2159Glu) 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 is not located to any known functional domain, and the Gln2159 amino acid residue occurs in an evolutionarily not constrained region (PMID: 29358731). The variant allele was found at a frequency of 7.9e-05 in 150946 control chromosomes, predominantly at a frequency of 0.00072 within the Latino subpopulation in the gnomAD database (v3.1 genomes dataset). This frequency is comparable to the maximum expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (0.00075), suggesting that the variant might be benign. The variant, c.6475C>G, has been reported in the literature in two Puerto Rican breast cancer patients (Diaz-Zabala_2018). However, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other 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 likely benign (n=2) or VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588031 SCV000887883 uncertain significance not provided 2020-02-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166819 SCV000903842 likely benign Hereditary cancer-predisposing syndrome 2017-05-11 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000076967 SCV000108764 benign Breast-ovarian cancer, familial 2 2013-09-24 no assertion criteria provided clinical testing

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