Submissions for variant NM_002878.4(RAD51D):c.82+1G>A

dbSNP: rs786202788

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165776	SCV000216521	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-08-31	criteria provided, single submitter	clinical testing	The c.82+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the RAD51D gene. This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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	RCV001377740	SCV001575149	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 1 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 ovarian cancer (PMID: 28888541). ClinVar contains an entry for this variant (Variation ID: 186222). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). 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.
Myriad Genetics, Inc.	RCV001377740	SCV004932366	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-03	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.