Submissions for variant NM_058216.3(RAD51C):c.376G>A (p.Ala126Thr)

gnomAD frequency: 0.00349  dbSNP: rs61758784

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000119170	SCV000153899	benign	Fanconi anemia complementation group O	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000212938	SCV000171271	benign	not specified	2014-04-03	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	RCV000129159	SCV000183887	benign	Hereditary cancer-predisposing syndrome	2014-07-28	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.
PreventionGenetics, part of Exact Sciences	RCV000212938	SCV000315331	likely benign	not specified		criteria provided, single submitter	clinical testing
Counsyl	RCV000119170	SCV000489839	likely benign	Fanconi anemia complementation group O	2016-06-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000411970	SCV000489840	likely benign	Breast-ovarian cancer, familial, susceptibility to, 3	2016-06-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129159	SCV000537389	benign	Hereditary cancer-predisposing syndrome	2015-10-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000658791	SCV000780586	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	RAD51C: BP4, BS2
Eurofins Ntd Llc (ga)	RCV000212938	SCV000854882	benign	not specified	2018-04-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212938	SCV000888596	benign	not specified	2020-08-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000119170	SCV001140714	likely benign	Fanconi anemia complementation group O	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000658791	SCV001474259	benign	not provided	2023-10-09	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000658791	SCV002010716	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798373	SCV002043686	benign	Breast and/or ovarian cancer	2019-05-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212938	SCV002066888	benign	not specified	2021-06-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129159	SCV002531812	benign	Hereditary cancer-predisposing syndrome	2020-05-20	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212938	SCV002551127	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000411970	SCV002761730	likely benign	Breast-ovarian cancer, familial, susceptibility to, 3	2020-10-19	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000411970	SCV004017245	benign	Breast-ovarian cancer, familial, susceptibility to, 3	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411970	SCV004043662	benign	Breast-ovarian cancer, familial, susceptibility to, 3	2023-05-10	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
True Health Diagnostics	RCV000129159	SCV000788200	likely benign	Hereditary cancer-predisposing syndrome	2017-12-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354932	SCV001549661	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51C p.Ala126Thr variant was identified in 70 of 11449 proband chromosomes (frequency: 0.006) from individuals or families with hereditary breast and ovarian cancer (Akbari_2010_20723205, Blanco_2014_25086635, Clague_2011_21980511, Coulet_2013_22725699, Jonson_2015_26740214, Kushnir_2012_23117857, Leeneer_2012_22370629, Lu_2012_22476429, Meindl_2009_20400964, Romero_2011_ 21537932, Scheckenbach_2014_24315737, Thompson_2012_21990120, Vuorela_2011_21750962, Wong_2011_21409391). The variant was also identified in dbSNP (ID: rs61758784) as “With other allele”, ClinVar (as likely benign by PreventionGenetics and Counsyl, as benign by Invitae, GeneDx, Ambry Genetics, Color Genomics, and Quest Diagnostics), Clinvitae (as benign and likely benign), LOVD 3.0 (9x), and Zhejiang Colon Cancer Database (2x). The variant was not identified in Cosmic or MutDB databases. The variant was identified in control databases in 955 of 275828 chromosomes (3 homozygous) at a frequency of 0.003462 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 28 of 23954 chromosomes (freq: 0.001169), Other in 31 (1 homozygous) of 6444 chromosomes (freq: 0.004811), Latino in 109 (1 homozygous) of 34292 chromosomes (freq: 0.003179), European (Non-Finnish) in 684 (1 homozygous) of 125890 chromosomes (freq: 0.005433), Ashkenazi Jewish in 43 of 10090 chromosomes (freq: 0.004262), European (Finnish) in 8 of 25752 chromosomes (freq: 0.000311), and South Asian in 52 of 30556 chromosomes (freq: 0.001702), while the variant was not observed in the East Asian populations. The variant is classified as a benign polymorphism in the literature (Akbari_2010_20723205, Clague_2011_21980511, Coulet_2013_22725699, Jonson_2015_26740214, Kushnir_2012_23117857, Leeneer_2012_22370629, Lu_2012_22476429, Meindl_2009_20400964, Osorio_2012_22451500). In vivo yeast functional studies have shown no detectable difference in expression versus the wild type allele (Clague_2011_21980511). In addition, Jonson (2015_26740214) has reported that the variant to be co-occurring in three individuals with a disease-causing RAD51C (c.945dupT), BRCA1 (p.Gln563Ter) or BRCA2 (c.5164_5165delAG) mutation, increasing the likelihood that the p.Ala126Thr variant does not have clinical significance. The p.Ala126Thr residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000658791	SCV001740781	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000212938	SCV001807201	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000658791	SCV001905908	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000658791	SCV001959252	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000658791	SCV002035818	likely benign	not provided		no assertion criteria provided	clinical testing