ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1124C>T (p.Pro375Leu)

gnomAD frequency: 0.00001  dbSNP: rs80358409
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000043741 SCV000071754 likely benign Hereditary breast ovarian cancer syndrome 2025-01-06 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 This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV001703941 SCV000521633 likely benign not provided 2021-04-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25111659, 22977638, 25896959, 28263838)
Color Diagnostics, LLC DBA Color Health 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 likely benign not specified 2021-11-29 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, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence 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 likely benign.
CeGaT Center for Human Genetics Tuebingen RCV001703941 SCV002497651 likely benign not provided 2022-01-01 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV002288542 SCV002579501 likely benign Familial cancer of breast 2024-02-09 criteria provided, single submitter clinical testing ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BS2_SUP; BP5_SUP, PM2_SUP
University of Washington Department of Laboratory Medicine, University of Washington RCV000219251 SCV003849849 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health RCV000077250 SCV004846866 benign Breast-ovarian cancer, familial, susceptibility to, 2 2023-09-05 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077250 SCV000109047 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2010-07-21 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077250 SCV000145816 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided clinical testing

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