Submissions for variant NM_002878.4(RAD51D):c.772_778del (p.Gly258fs)

dbSNP: rs1064795045

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486183	SCV000570461	likely pathogenic	not provided	2021-10-20	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation as the last 71 amino acids are replaced with 49 different amino acids; Observed in at least one individual with ovarian cancer (Carter 2018); Published functional studies demonstrate a damaging effect: sensitivity to platinum-based chemotherapy and PARP inhibitors (Kondrashova 2017); Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 30322717, 14704354, 19327148, 21111057, 28588062)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531216	SCV000651779	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly258Serfs*50) in the RAD51D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 71 amino acid(s) of the RAD51D protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ovarian tumor (PMID: 30322717). ClinVar contains an entry for this variant (Variation ID: 421303). This variant disrupts the ATPase domain and RAD51C interaction domain of the RAD51D protein, which are necessary for the DNA repair activity (PMID: 14704354, 19327148, 21111057, 10749867). While functional studies have not been performed to directly test the effect of this variant on RAD51D protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000560925	SCV000671950	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-13	criteria provided, single submitter	clinical testing	The c.772_778delGGGAGGC variant, located in coding exon 9 of the RAD51D gene, results from a deletion of 7 nucleotides at nucleotide positions 772 to 778, causing a translational frameshift with a predicted alternate stop codon (p.G258Sfs*50). This alteration occurs at the 3' terminus of theRAD51D, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 71 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in an individual with high grade ovarian carcinoma (Kondrashova O et al. Cancer Discov 2017 09;7(9):984-998). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000560925	SCV001339934	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This variant deletes 7 nucleotides in exon 9 of the RAD51D gene, creating a frameshift and premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein. This variant is expected to disrupt the amino acid residues Gly258 through Thr328 of the RAD51D protein that encode the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057) and RAD51C interaction domain (PMID: 10749867, 14704354, 19327148). Although functional studies have not been reported for this variant, this variant is likely to disrupt RAD51D function. This variant has been reported in a few individuals affected with ovarian cancer (PMID: 30322717; Color internal data). 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 Likely Pathogenic.
Myriad Genetics, Inc.	RCV000531216	SCV004189565	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2023-11-30	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000531216	SCV004200427	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2022-12-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000531216	SCV005640002	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-04-15	criteria provided, single submitter	clinical testing