Submissions for variant NM_002878.4(RAD51D):c.141C>G (p.Tyr47Ter)

dbSNP: rs771077929

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794886	SCV000934320	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-06-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr47*) in the RAD51D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 641610). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003584750	SCV004357180	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 2 of the RAD51D gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 24240112). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51D function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV000794886	SCV004932359	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-04	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000794886	SCV001549198	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4		no assertion criteria provided	clinical testing	The RAD51D p.Tyr47X variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, Cosmic, or the Zhejiang University Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.141C>G variant leads to a premature stop codon at position 47 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the RAD51D gene are an established mechanism of disease in the RAD51D associated cancer and is the type of variant expected to cause the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.