Submissions for variant NM_002878.4(RAD51D):c.904-2A>T

dbSNP: rs1403784434

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540056	SCV000651794	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 9 of the RAD51D gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with biliary cancer, ovarian cancer and retroperitoneal leiomyosarcoma (PMID: 29020732, 34838098). This variant is also known as c.964-2A>T. ClinVar contains an entry for this variant (Variation ID: 472631). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. 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	RCV000562807	SCV000674697	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-06-12	criteria provided, single submitter	clinical testing	The c.904-2A>T intronic variant results from an A to T substitution two nucleotides upstream from coding exon 10 in the RAD51D gene. This alteration was seen in a patient diagnosed with ovarian cancer at age 58 (Eoh KJ et al. Cancer Res Treat. 2017 Sep). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA analyses have shown that this alteration leads to an aberrant splicing by activation of cryptic acceptor site (Casadei S et al. Proc. Natl. Acad. Sci. U.S.A., 2019 Dec; Ambry internal data). The resulting transcript is predicted not to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, structural analysis suggests that this region contains a highly conserved ATP cap, which functions to hold the ATP in place and is likely to impact nucleoprotein filament stability (Amunugama R et al. J. Biol. Chem. 2012 Mar; 287(12):8724-36). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000562807	SCV000686499	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This variant causes an A to T nucleotide substitution at the canonical -2 position of intron 9 splice acceptor site of the RAD51D gene. A RNA study has shown that this variant results in the use of cryptic splice acceptor site which then cause a deletion of 7 nucleotides from the beginning of exon 9 (c.904_910del) (PMID: 31843900). The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein (p.Pro302Valfs*6) that lacks the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057) and RAD51C interaction domain (PMID: 10749867, 14704354, 19327148). Although protein functional studies have not been reported, this variant is likely to disrupt RAD51D function. This variant has been reported in individuals affected with ovarian cancer (PMID: 29020732), breast and ovarian cancer (PMID: 26046366), leiomyosarcoma (PMID: 34838098), and pancreatic ductal adenocarcinoma (PMID: 37024097). This variant has been identified in 1/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030588	SCV001193725	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001030588	SCV001338494	pathogenic	Hereditary breast ovarian cancer syndrome	2022-07-28	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.904-2A>T alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splice acceptor site. Four predict the variant strengthens an alternate cryptic exonic 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251488 control chromosomes. c.904-2A>T has been reported in the literature in individuals affected with a variety of cancers such as Peritoneum Leiomyosarcoma (Futagawa_2021), Biliary tract cholangiocarcinoma (Wardell_2018), Breast carcinoma (Kaneyasu_2020, Johnston_2015) and Ovarian serous carcinoma (Eoh_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/Likely pathogenic, n=4; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000540056	SCV004200355	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2023-09-19	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV001171472	SCV001251384	pathogenic	Hereditary site-specific ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research
Laboratory for Genotyping Development, RIKEN	RCV003159903	SCV002758188	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research