ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1124C>T (p.Pro375Leu) (rs80358409)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043741 SCV000071754 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000219251 SCV000273170 likely benign Hereditary cancer-predisposing syndrome 2019-01-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000423315 SCV000521633 likely benign not specified 2017-06-14 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.
Color Health, Inc RCV000219251 SCV000911092 benign Hereditary cancer-predisposing syndrome 2016-02-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000423315 SCV001339186 uncertain significance not specified 2020-03-02 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1124C>T (p.Pro375Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250164 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1124C>T has been reported in the literature in individuals referred for BRCA mutational screening (examples- DeSilva_2011, Tram_2013, Maier_2014, DArgenio_2015, Zanella_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with another pathogenic variant has been reported (BRCA1 c.66_67delAG, p.Leu22_Glu23LeuValfs; BIC database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharing Clinical Reports Project (SCRP) RCV000077250 SCV000109047 likely benign Breast-ovarian cancer, familial 2 2010-07-21 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077250 SCV000145816 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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