ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9925G>A (p.Glu3309Lys) (rs80359251)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080047 SCV000073929 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130750 SCV000185641 likely benign Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing No disease association in small case-control study;In silico models in agreement (benign)
GeneDx RCV000120378 SCV000210521 likely benign not specified 2017-07-10 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000195387 SCV000296744 likely benign not provided 2018-10-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120378 SCV000695283 likely benign not specified 2020-08-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9925G>A (p.Glu3309Lys) 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 8.1e-05 in 282626 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.9925G>A, has been reported in the literature in individuals affected with cancer, including breast cancer and lung adenocarcinoma (Pal_2015, Lu_2015, Mandelker_2017, Parry_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with a pathogenic variant has been reported (BRCA2 c.7110dupA , p.Ser2371fsX21; internal testing), providing supporting evidence for a benign role. c.9925G>A has been reported in the FLOSSIES database in 9 women older than age 70 years who have never had cancer, providing further supporting evidence for a benign role. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Ghosh_2015). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=5 and uncertain significance, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000130750 SCV000902904 likely benign Hereditary cancer-predisposing syndrome 2015-11-16 criteria provided, single submitter clinical testing
Mendelics RCV000112824 SCV001139279 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000120378 SCV000084530 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000112824 SCV000145732 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112824 SCV000297582 benign Breast-ovarian cancer, familial 2 2009-12-17 no assertion criteria provided clinical testing

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