Submissions for variant NM_002878.4(RAD51D):c.196G>A (p.Val66Met)

gnomAD frequency: 0.00009  dbSNP: rs56026142

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130161	SCV000184996	likely benign	Hereditary cancer-predisposing syndrome	2018-09-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000225779	SCV000287700	benign	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-28	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238834	SCV000297127	uncertain significance	not specified	2015-07-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000225779	SCV000489108	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2016-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000238834	SCV000515953	likely benign	not specified	2017-10-11	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	RCV000130161	SCV000686426	likely benign	Hereditary cancer-predisposing syndrome	2015-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000238834	SCV000920125	benign	not specified	2020-10-15	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.196G>A (p.Val66Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 251384 control chromosomes, predominantly at a frequency of 0.0036 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 29 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00013). In addition, allele frequency of this variant in 8380 Japanese controls is 0.0137 (jMorp database). These data strongly suggest that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.196G>A has been reported in the literature in individuals affected with various types of cancer (Lu_2015, Yurgelun_2017, Hauke_2018, Wei_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.571_572insAT, p.D191fs, Wei_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=4, VUS n=3). Based on the evidence outlined above, the variant was classified as benign.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030594	SCV001193731	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284344	SCV001470086	likely benign	not provided	2022-08-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798441	SCV002043215	likely benign	Breast and/or ovarian cancer	2021-06-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130161	SCV002534780	likely benign	Hereditary cancer-predisposing syndrome	2021-03-01	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000225779	SCV004017746	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-04-06	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000238834	SCV004024299	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952682	SCV004770072	likely benign	RAD51D-related condition	2019-07-16	criteria provided, single submitter	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).
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001284344	SCV001959803	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001284344	SCV001963752	likely benign	not provided		no assertion criteria provided	clinical testing