Submissions for variant NM_058216.3(RAD51C):c.627T>G (p.Tyr209Ter)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003508081	SCV004368357	pathogenic	Fanconi anemia complementation group O	2024-07-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr209*) 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004368981	SCV004931197	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.
Ambry Genetics	RCV004368982	SCV005030266	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	The p.Y209* pathogenic mutation (also known as c.627T>G), located in coding exon 4 of the RAD51C gene, results from a T to G substitution at nucleotide position 627. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. 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; however, direct evidence is insufficient at this time (Ambry internal data). As such, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV004736343	SCV005344279	likely pathogenic	RAD51C-related disorder	2024-03-20	no assertion criteria provided	clinical testing	The RAD51C c.627T>G variant is predicted to result in premature protein termination (p.Tyr209*). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in RAD51C are expected to be pathogenic. This variant is interpreted as likely pathogenic.