Submissions for variant NM_002878.4(RAD51D):c.919G>A (p.Glu307Lys)

gnomAD frequency: 0.00083  dbSNP: rs115031549

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656966	SCV000149730	likely benign	not provided	2021-03-07	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: 25186627, 28864920)
Ambry Genetics	RCV000115821	SCV000185235	likely benign	Hereditary cancer-predisposing syndrome	2018-09-05	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	RCV000989829	SCV000287733	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656966	SCV000602170	likely benign	not provided	2023-02-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000656966	SCV000859940	uncertain significance	not provided	2018-03-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115821	SCV000910718	benign	Hereditary cancer-predisposing syndrome	2015-11-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212975	SCV000918142	benign	not specified	2018-07-31	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.919G>A (p.Glu307Lys) results in a conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was found in 78/277234 control chromosomes in gnomAD, but was observed primarily in the African subpopulation (70/24038 control chromosomes). The frequency within the African control individuals is more than 23-fold above the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer phenotype (0.00013). In addition, this variant has been found in 21/2559 African American women who are 70 years old or older and are cancer-free. These evidence strongly suggests that the variant is a benign polymorphism found primarily in populations of African origin. c.919G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments including uncertain significance (2x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV004700423	SCV001140404	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Sema4, Sema4	RCV000115821	SCV002527051	likely benign	Hereditary cancer-predisposing syndrome	2021-04-13	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149803	SCV003838853	likely benign	Breast and/or ovarian cancer	2021-09-21	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354385	SCV001548991	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	RAD51D, EXON10, c.919G>A, p.Glu307Lys, Heterozygous, Likely Benign The RAD51D p.Glu307Lys variant was identified in 2 of 4316 proband chromosomes (frequency: 0.0005) from individuals or families with breast cancer (Tung 2015). The variant was also identified in dbSNP (ID: rs115031549) as "With Uncertain Significance allele", in ClinVar with Conflicting interpretations of pathogenicity (as Benign by Integrated Genetics and Colour, as Likely benign by Invitae and Ambry and as Uncertain significance by Mendelics, Quest, GeneDx and EGL Genetics). The variant was identified in control databases in 78 of 277234 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 70 of 24038 chromosomes (freq: 0.003), Other in 1 of 6468 chromosomes (freq: 0.0002), Latino in 7 of 34420 chromosomes (freq: 0.0002), but was not observed in the European Non-Finnish, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Glu307 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. Assessment Date: 2019/07/29
PreventionGenetics, part of Exact Sciences	RCV003905100	SCV004726551	likely benign	RAD51D-related disorder	2022-02-11	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).