Submissions for variant NM_002878.4(RAD51D):c.695G>A (p.Arg232Gln)

gnomAD frequency: 0.00457  dbSNP: rs28363283

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212966	SCV000171274	benign	not specified	2014-02-11	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.
Ambry Genetics	RCV000127695	SCV000213965	benign	Hereditary cancer-predisposing syndrome	2014-08-07	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000205175	SCV000261683	benign	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000205175	SCV000488478	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2016-06-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000127695	SCV000686481	benign	Hereditary cancer-predisposing syndrome	2014-12-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212966	SCV000806584	benign	not specified	2017-06-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212966	SCV000889831	benign	not specified	2021-07-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212966	SCV002071922	benign	not specified	2019-09-11	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212966	SCV002760912	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149871	SCV003838193	benign	Breast and/or ovarian cancer	2022-05-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000205175	SCV004017712	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 has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000205175	SCV004562855	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2023-09-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000760068	SCV004811051	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	RAD51D: BP4, BS1
Breakthrough Genomics, Breakthrough Genomics	RCV000760068	SCV005214639	likely benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000127695	SCV000788208	likely benign	Hereditary cancer-predisposing syndrome	2017-09-13	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357198	SCV001552586	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51D p.Arg232Gln variant was identified in 16 of 10424 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer, ovarian cancer, primary myelofibrosis or lynch syndrome and was not identified in 2120 control chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Loveday 2011, Pratz 2016, Tung 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs28363283) as "With other allele", and in ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Color Genomics, Quest Diagnostics Nichols Institute San Juan Capistrano; as likely benign by Counsyl). The variant was not identified in the Cosmic database. The variant was identified in control databases in 418 of 271350 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 328 of 23508 chromosomes (freq: 0.01), Other in 7 of 6346 chromosomes (freq: 0.001), Latino in 48 of 33802 chromosomes (freq: 0.001), European in 20 of 123952 chromosomes (freq: 0.0002), Ashkenazi Jewish in 14 of 9952 chromosomes (freq: 0.001), and South Asian in 1 of 30008 chromosomes (freq: 0.00003); it was not observed in the East Asian, and Finnish populations. The p.Arg232 residue is conserved in mammals but not in more distantly related organisms however four out of five 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, HumanSpliceFinder) do not predict a difference in splicing. This variant was identified in an individual with HBOC and a co-occurring BRCA2 variant (c.6405_6409del) increasing the likelihood the RAD51D c.695G>A variant may not have clinical significance. 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000212966	SCV001906392	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000212966	SCV001929391	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000760068	SCV001960038	likely benign	not provided		no assertion criteria provided	clinical testing