Submissions for variant NM_058216.3(RAD51C):c.630T>G (p.Tyr210Ter)

dbSNP: rs786201909

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164432	SCV000215071	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-14	criteria provided, single submitter	clinical testing	The p.Y210* pathogenic mutation (also known as c.630T>G) located in coding exon 4 of the RAD51C gene, results from a T to G substitution at nucleotide position 630. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529934	SCV000650019	pathogenic	Fanconi anemia complementation group O	2024-05-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr210*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 185074). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657719	SCV000779468	pathogenic	not provided	2018-11-07	criteria provided, single submitter	clinical testing	This variant is denoted RAD51C c.630T>G at the cDNA level and p.Tyr210Ter (Y210X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in at least one individual undergoing multi-gene panel testing (LaDuca 2017) and is considered pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000164432	SCV001340645	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-14	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 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 reported in an individual affected with ovarian cancer (PMID: 30128536). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194263	SCV001363655	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-25	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.630T>G (p.Tyr210X) 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 was absent in 251252 control chromosomes (gnomAD) but has been reported in the literature in an individual affected with ovarian cancer (Lu_2018) and an unknown phenotype (LaDuca_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798584	SCV002043691	likely pathogenic	Breast and/or ovarian cancer	2019-12-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467296	SCV004208059	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2021-04-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657719	SCV004220150	pathogenic	not provided	2023-06-22	criteria provided, single submitter	clinical testing	The RAD51C c.630T>G (p.Tyr210*) variant causes the premature termination of RAD51C protein synthesis. This variant has been reported in the published literature in an individual with ovarian cancer (PMID: 30128536 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003467296	SCV004932335	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2024-01-03	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.