Submissions for variant NM_002878.4(RAD51D):c.83-4_83-3delinsAG

dbSNP: rs2091789505

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001189453	SCV001356747	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-02	criteria provided, single submitter	clinical testing	This variant causes a TC>AG multiple nucleotide substitution at the -4 to -3 position of intron 1 of the RAD51D gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant may result in an absent or disrupted protein product. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001371352	SCV001567911	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the RAD51D gene. It does not directly change the encoded amino acid sequence of the RAD51D protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. 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: 926681). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001189453	SCV002675333	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-27	criteria provided, single submitter	clinical testing	The c.83-4_83-3delTCinsAG intronic variant, results from a TC to AG substitution three and four nucleotides upstream from coding exon 2 of the RAD51D gene. This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV001371352	SCV004200446	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2021-12-10	criteria provided, single submitter	clinical testing