Submissions for variant NM_002878.4(RAD51D):c.739-1G>A

gnomAD frequency: 0.00001  dbSNP: rs1555567202

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565653	SCV000663830	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-15	criteria provided, single submitter	clinical testing	The c.739-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 9 of the RAD51D gene. This alteration was observed in 1 of 5054 African American women diagnosed with breast cancer (Palmer JR et al. J Natl Cancer Inst, 2020 Dec;112:1213-1221). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800335	SCV000940043	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-12-06	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 of the RAD51D gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast or lung cancer (PMID: 32427313, 36113475). ClinVar contains an entry for this variant (Variation ID: 480532). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx	RCV003322790	SCV004028108	likely pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with breast cancer in published literature (Palmer et al., 2020); This variant is associated with the following publications: (PMID: 36113475, 19327148, 14704354, 21111057, 32427313)
Myriad Genetics, Inc.	RCV000800335	SCV004933257	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-05	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Baylor Genetics	RCV000800335	SCV005054028	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-03	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354651	SCV001549317	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51D c.739-1G>A variant was not identified in the literature nor was it identified in the dbSNP, Clinvitae, Cosmic, and Zhejiang Colon Cancer Database. The variant was identified in ClinVar (as likely pathogenic by Ambry Genetics). 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.739-1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.