Submissions for variant NM_058216.3(RAD51C):c.397C>T (p.Gln133Ter)

dbSNP: rs387907159

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205139	SCV000260887	pathogenic	Fanconi anemia complementation group O	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln133*) in the RAD51C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). This variant is present in population databases (rs387907159, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21990120, 22538716). ClinVar contains an entry for this variant (Variation ID: 31556). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000219684	SCV000274438	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-12	criteria provided, single submitter	clinical testing	The p.Q133* pathogenic mutation (also known as c.397C>T), located in coding exon 2 of the RAD51C gene, results from a C to T substitution at nucleotide position 397. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This mutation has been identified in multiple breast and/or ovarian cancer families (Thompson ER et al. Hum. Mutat. 2012 Jan;33:95-9; Loveday C et al. Nat. Genet. 2012 Apr;44:475-6; author reply 476; Crawford B et al. Breast Cancer Res. Treat. 2017 Jun;163:383-390), and in a pancreatic cancer patient (Hu C et al. JAMA. 2018 06;319:2401-2409). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000205139	SCV000489817	pathogenic	Fanconi anemia complementation group O	2016-06-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000024264	SCV000489818	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2016-06-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000483994	SCV000567793	pathogenic	not provided	2024-07-30	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29922827, 28888541, 22538716, 25470109, 21990120, 28281021, 23117857, 32885271, 33804961, 29625052, 34887416, 36451132, 31784482)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004576911	SCV000699808	pathogenic	Hereditary breast ovarian cancer syndrome	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.397C>T (p.Gln133X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250888 control chromosomes (gnomAD). c.397C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (examples: Hu_2018, Loveday_2012, Thompson_2011) including a family in which an unaffected individual carried the variant suggesting reduced penetrance (Thompson_2011). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29922827, 22538716, 21990120). ClinVar contains an entry for this variant (Variation ID: 31556). Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000219684	SCV001350188	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 2 of the RAD51C gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/247914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149575	SCV003837697	pathogenic	Breast and/or ovarian cancer	2021-11-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000024264	SCV004017772	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-06	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000024264	SCV004207943	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-09-10	criteria provided, single submitter	clinical testing
OMIM	RCV000024264	SCV000045555	risk factor	Breast-ovarian cancer, familial, susceptibility to, 3	2012-04-26	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV000483994	SCV001365256	pathogenic	not provided	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	RCV000024264	SCV001550219	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3		no assertion criteria provided	clinical testing	The RAD51C p.Gln133* variant was identified in 3 of 2450 proband chromosomes (frequency: 0.001) from individuals or families with ovarian or breast cancer and was not identified in 854 control chromosomes from healthy individuals (Loveday 2012, Thompson 2012). The variant was also identified in dbSNP (ID: rs387907159) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and three other submitters) and LOVD 3.0, databases. The variant was identified in control databases in 1 of 242778 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 109692 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gln133* variant leads to a premature stop codon at position 133, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the RAD51C gene are an established mechanism of disease in RAD51C associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.