Submissions for variant NM_002878.4(RAD51D):c.983C>T (p.Thr328Ile)

gnomAD frequency: 0.00021  dbSNP: rs138969595

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129828	SCV000184643	likely benign	Hereditary cancer-predisposing syndrome	2018-11-05	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.
GeneDx	RCV000859034	SCV000211662	likely benign	not provided	2020-11-19	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function This variant is associated with the following publications: (PMID: 25980754)
Counsyl	RCV000411668	SCV000488575	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2016-06-09	criteria provided, single submitter	clinical testing
Invitae	RCV000411668	SCV000551327	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129828	SCV000902869	likely benign	Hereditary cancer-predisposing syndrome	2016-04-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000859034	SCV001134809	likely benign	not provided	2022-12-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000411668	SCV001140402	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254688	SCV001363868	benign	not specified	2019-07-18	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.983C>T (p.Thr328Ile) 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 0.00011 in 282876 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.983C>T, has been reported in the literature in individuals affected with Lynch syndromeassociated cancer and/or polyps (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a BRCA1 pathogenic variant has been reported (c.3598C>T, p.Gln1200X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions (evaluation after 2014) cite the variant four times as likely benign and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000129828	SCV002527059	likely benign	Hereditary cancer-predisposing syndrome	2021-11-05	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411668	SCV004017733	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.
PreventionGenetics, part of Exact Sciences	RCV003935215	SCV004749312	likely benign	RAD51D-related condition	2019-06-11	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).