Submissions for variant NM_058216.3(RAD51C):c.195A>G (p.Arg65=)

gnomAD frequency: 0.00105  dbSNP: rs45511291

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123371	SCV000166694	benign	Fanconi anemia complementation group O	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000212935	SCV000171270	benign	not specified	2014-03-05	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	RCV000129169	SCV000183902	benign	Hereditary cancer-predisposing syndrome	2014-11-27	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.
Illumina Laboratory Services, Illumina	RCV000336178	SCV000404321	likely benign	Fanconi anemia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000402152	SCV000404322	likely benign	Breast and Ovarian Cancer Susceptibility	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000123371	SCV000489819	benign	Fanconi anemia complementation group O	2016-05-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000411807	SCV000489820	benign	Breast-ovarian cancer, familial, susceptibility to, 3	2016-05-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129169	SCV000686331	benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588599	SCV000699798	benign	not provided	2016-06-27	criteria provided, single submitter	clinical testing	Variant summary: The RAD51C c.195A>G (p.Arg65Arg) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 354/122132 control chromosomes (13 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.0396715 (343/8646). This frequency is about 635 times the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant has been reported in HBOC families, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212935	SCV000888595	benign	not specified	2021-09-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588599	SCV001474182	benign	not provided	2019-08-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212935	SCV002072248	benign	not specified	2021-04-16	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212935	SCV002551126	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149848	SCV003837696	benign	Breast and/or ovarian cancer	2021-11-09	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000411807	SCV004017251	benign	Breast-ovarian cancer, familial, susceptibility to, 3	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411807	SCV004019908	benign	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Leiden Open Variation Database	RCV000212935	SCV001365249	likely benign	not specified	2011-08-25	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355882	SCV001550896	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	RAD51C, EXON 02, c.195A>G, p.Arg65=, Heterozygous, Benign The RAD51C p.Arg65= variant was identified in 4 of 5232 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancers of Australian and Danish ethnicity and was not identified in 427 control chromosomes from healthy individuals (Jonson 2015, Thompson 2012). The variant was also identified in dbSNP (ID: rs45511291) as “With Likely benign allele”; in the ClinVar and Clinvitae database as benign by Invitae, GeneDx, Ambry Genetics, and Counsyl, and likely benign by Illumina; and in the LOVD 3.0 database 2X with the following statistical data given: 2 of 1053 (freq.=0.002) and 1 of 134 (freq.0.003). The variant was further identified in the 1000 Genomes Project in 41 of 5000 chromosomes (frequency: 0.001); in HAPMAP-EAS in 40 of 1008 chromosomes (frequency: 0.04), HAPMAP-AFR in 1 of 1322 chromosomes (frequency: 0.0001) and the NHLBI GO Exome Sequencing Project in 1 of 8600 European American and in 5 of 4406 African American alleles. The variant was not identified in the Cosmic and MutDB, databases. The variant was identified in control databases in 773 of 277228 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following population at a frequency greater than 1%: East Asian in 748 of 18868 chromosomes (freq: 0.04). The p.Arg65= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. REFERENCES: Jønson L, Ahlborn LB, Steffensen AY, Djursby M, Ejlertsen B, Timshel S,Nielsen FC, Gerdes AM, Hansen TV. Identification of six pathogenic RAD51Cmutations via mutational screening of 1228 Danish individuals with increased riskof hereditary breast and/or ovarian cancer. Breast Cancer Res Treat. 2016Jan;155(2):215-22. doi: 10.1007/s10549-015-3674-y. Epub 2016 Jan 6. PubMed PMID: 26740214. Thompson ER, Boyle SE, Johnson J, Ryland GL, Sawyer S, Choong DY, kConFab,Chenevix-Trench G, Trainer AH, Lindeman GJ, Mitchell G, James PA, Campbell IG.Analysis of RAD51C germline mutations in high-risk breast and ovarian cancerfamilies and ovarian cancer patients. Hum Mutat. 2012 Jan;33(1):95-9. doi:10.1002/humu.21625. Epub 2011 Nov 4. PubMed PMID: 21990120.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588599	SCV001957508	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000212935	SCV001967901	benign	not specified		no assertion criteria provided	clinical testing