Submissions for variant NM_002878.4(RAD51D):c.145-4G>A

gnomAD frequency: 0.00006  dbSNP: rs201361465

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129971	SCV000184795	likely benign	Hereditary cancer-predisposing syndrome	2019-08-04	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.
Counsyl	RCV000410222	SCV000489684	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2016-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000760060	SCV000528369	likely benign	not provided	2020-12-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410222	SCV000561558	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129971	SCV000686421	likely benign	Hereditary cancer-predisposing syndrome	2016-09-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000760060	SCV000889819	likely benign	not provided	2023-06-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000760060	SCV001502230	likely benign	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129971	SCV002534773	likely benign	Hereditary cancer-predisposing syndrome	2021-07-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267872	SCV002550928	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267872	SCV002766209	likely benign	not specified	2022-11-21	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.145-4G>A 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. 4/4 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 0.00012 in 251078 control chromosomes (gnomAD). This frequency is close to the predicted frequency for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome (0.00012 vs 0.00013), strongly suggesting the variant may be benign. To our knowledge, no occurrence of c.145-4G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Nine 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 likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149896	SCV003838854	uncertain significance	Breast and/or ovarian cancer	2021-07-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410222	SCV004017751	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2023-04-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000760060	SCV001743967	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000760060	SCV001955820	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894993	SCV004713617	likely benign	RAD51D-related disorder	2022-03-10	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).