Submissions for variant NM_058216.3(RAD51C):c.186A>G (p.Gln62=)

gnomAD frequency: 0.00322  dbSNP: rs28363303

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212933	SCV000171269	benign	not specified	2014-03-14	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	RCV000131123	SCV000186054	benign	Hereditary cancer-predisposing syndrome	2014-11-25	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000203729	SCV000261112	benign	Fanconi anemia complementation group O	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212933	SCV000315330	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000203729	SCV000404319	likely benign	Fanconi anemia complementation group O	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000412091	SCV000404320	likely benign	Breast-ovarian cancer, familial, susceptibility to, 3	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Counsyl	RCV000203729	SCV000489811	benign	Fanconi anemia complementation group O	2016-05-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000412091	SCV000489812	benign	Breast-ovarian cancer, familial, susceptibility to, 3	2016-05-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131123	SCV000686330	benign	Hereditary cancer-predisposing syndrome	2015-08-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586849	SCV000699797	benign	not provided	2016-07-01	criteria provided, single submitter	clinical testing	Variant summary: The c.186A>G (p.GLn62=) in RAD51C gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.001(123/121184 chrs tested), predominantly in individuals of African origin (0.01; 117/10292 control chrs). This frequency greatly exceeds the maximal expected frequency of a pathogenic allele (0.00006) in this gene. The variant of interest has been reported in several affected individuals in co-occurrence with known pathogenic variant in BRCA2 gene in at least 1HBOC family. In addition, the variant has been classified as Benign by reputable databases/clinical laboratory. Taking together, the variant was classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586849	SCV000888594	benign	not provided	2022-08-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212933	SCV002066303	likely benign	not specified	2021-10-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586849	SCV003800454	benign	not provided	2022-04-30	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000412091	SCV004017248	benign	Breast-ovarian cancer, familial, susceptibility to, 3	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412091	SCV004019907	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492576	SCV004239987	benign	Breast and/or ovarian cancer	2022-11-09	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212933	SCV004242881	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000131123	SCV000788199	likely benign	Hereditary cancer-predisposing syndrome	2017-09-13	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355321	SCV001550179	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51C p.Gln62= variant was identified in 3 of 4196 proband chromosomes (frequency: 0.001) from American, Danish and Spanish individuals or families with non-BRCA1/2 hereditary breast/ovarian cancer (Zheng_2010_20697805, Romero_2011_21537932, Jonson_2015_26740214, Clague_2011_21980511). In 1 proband, the variant co-occurred with a disease-causing BRCA2 mutation (p.Lys172Lys) (Jonson_2015_26740214). The variant was also identified in dbSNP (ID: rs28363303) “With Likely benign allele”, ClinVar (classified benign by GeneDx, Ambry Genetics, Invitae, Prevention Genetics, Counsyl, and likely benign by Illumina, and Quest Diagnostics Nichols Institute San Juan), and Clinvitae (6x) but was not identified in Cosmic, MutDB, or LOVD 3.0. The variant was identified in control databases in 279 (1 homozygous) of 277224 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 254 of 24038 chromosomes (freq: 0.01), Latino in 18 of 34420 chromosomes (freq: 0.0005), European Non-Finnish in 5 of 126712 chromosomes (freq: 0.00004), and South Asian in 2 of 30776 chromosomes (freq: 0.00007), while not observed in the Other, Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Gln62= 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.