Submissions for variant NM_002878.4(RAD51D):c.765G>A (p.Arg255=)

gnomAD frequency: 0.00003  dbSNP: rs751833940

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232217	SCV000287722	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562729	SCV000667141	likely benign	Hereditary cancer-predisposing syndrome	2015-07-24	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.
Color Diagnostics, LLC DBA Color Health	RCV000562729	SCV000686485	likely benign	Hereditary cancer-predisposing syndrome	2017-03-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001711634	SCV000729705	likely benign	not provided	2020-05-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000600096	SCV001362753	likely benign	not specified	2019-04-25	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.765G>A 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 allele was found at a frequency of 4e-06 in 251300 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.765G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (APC c.4393_4394dupAG , p.Ser1465fsX9), providing supporting evidence for a benign role. 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.
Sema4, Sema4	RCV000562729	SCV002534853	likely benign	Hereditary cancer-predisposing syndrome	2021-07-20	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003977659	SCV004786300	likely benign	RAD51D-related disorder	2022-02-24	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).