ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.517-4C>G (rs81002804)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044590 SCV000072603 benign not provided 2019-03-01 criteria provided, single submitter clinical testing
GeneDx RCV000212206 SCV000167325 benign not specified 2014-04-07 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.
Ambry Genetics RCV000131488 SCV000186476 likely benign Hereditary cancer-predisposing syndrome 2018-06-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Other data supporting benign classification
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044590 SCV000296597 benign not provided 2018-12-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212206 SCV000694837 uncertain significance not specified 2019-05-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.517-4C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.5e-05 in 282876 control chromosomes, predominantly at a frequency of 0.00036 within the African or African-American subpopulation in the gnomAD database. This frequency is somewhat lower than the expected maximum for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00075); therefore the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.517-4C>G variant has been reported in the literature in individuals affected with breast cancer (Pal_2015, Abulkhair_2018) and also in controls (Wagner_1999), but without strong evidence for or against causality. These reports therefore do 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. Five other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (3x), benign (1x) or VUS (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl RCV000113731 SCV000785180 likely benign Breast-ovarian cancer, familial 2 2017-05-22 criteria provided, single submitter clinical testing
Color RCV000131488 SCV000903207 likely benign Hereditary cancer-predisposing syndrome 2015-08-11 criteria provided, single submitter clinical testing
Mendelics RCV000113731 SCV001138969 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113731 SCV000147051 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113731 SCV000297535 benign Breast-ovarian cancer, familial 2 2012-09-11 no assertion criteria provided clinical testing

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