Submissions for variant NM_058216.3(RAD51C):c.744T>C (p.Phe248=)

gnomAD frequency: 0.00016  dbSNP: rs150142859

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164771	SCV000215447	likely benign	Hereditary cancer-predisposing syndrome	2014-12-24	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198935	SCV000253643	likely benign	Fanconi anemia complementation group O	2024-12-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000442055	SCV000518186	likely benign	not specified	2017-05-24	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 Diagnostics, LLC DBA Color Health	RCV000164771	SCV000686382	likely benign	Hereditary cancer-predisposing syndrome	2015-12-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442055	SCV000699823	benign	not specified	2018-07-10	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.744T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was found in the gnomAD database at an overall frequency of 0.0000433, but was observed exclusively in the African subpopulation at a frequency of 0.0005. This frequency within African control individuals is approximately 8-fold above the estimated maximal expected allele frequency for a pathogenic variant in RAD51C causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.744T>C has been reported in the literature in one individual affected with Hereditary Breast and Ovarian Cancer. However, this report does not provide strong evidence for pathogenicity. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800488	SCV002046527	likely benign	not provided	2023-07-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164771	SCV002530010	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004535104	SCV004756342	likely benign	RAD51C-related disorder	2019-06-04	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).