Submissions for variant NM_002878.4(RAD51D):c.2dup (p.Met1fs)

dbSNP: rs772306012

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561635	SCV000663852	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	The c.2dupT pathogenic mutation (also known as p.M1?) is located in coding exon 1 of the RAD51D gene and results from a duplication of T at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). Although this alteration is expected to disrupt the translation initiation site, the RAD51D gene contains a second in frame methionine at amino acid position 16. This has the potential to function as an alternate translation initiation site, resulting in the removal of the first 15 amino acids from the protein. Based on structural analysis, the first 15 amino acids are predicted to play an important role in protein function (Kim YM et al. Int. J. Biochem. Cell Biol., 2011 Mar;43:416-22). While this exact alteration has not been reported in the literature, similar alterations impacting the initiation codon (c.1A>T and c.1A>G) have been detected in individuals with breast or ovarian cancer (Gutiérrez-Enríquez S et al. Int. J. Cancer, 2014 May;134:2088-97; Susswein LR et al. Genet. Med., 2016 Aug;18:823-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000561635	SCV000691324	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-07	criteria provided, single submitter	clinical testing	This variant results in the loss of translation initiator codon of the RAD51D gene. Although functional studies have not been reported, this variant is expected to result in an absent or non-functional protein product. It has been shown that the highly conserved RAD51D N-terminus (a.a. 1-83) encodes the single-stranded DNA binding domain and that the 13-residue N-terminal tail (a.a. 1-13) contributes to proper protein folding via hydrophobic interactions between side chains of the N-terminal tail and alpha helices of the single-stranded DNA binding domain (PMID: 21111057). These findings suggest that the production of a full-length protein from p.Met1 is important for RAD51 function. While an in-frame methionine occurs at codon 16, it is not known if it can serve as an alternative translation initiation site to produce a functional RAD51D protein. This variant has not been reported in individuals affected with hereditary cancer in the literature. However, different variants that also disrupt p.Met1 (c.1A>G and c.1A>T) have been reported in individuals affected with ovarian cancer (ClinVar variation ID: 127884 and 419798). This variant has been identified in 1/246458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001210928	SCV001382444	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-09-10	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the RAD51D mRNA. The next in-frame methionine is located at codon 16. This variant is present in population databases (rs772306012, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24130102, 26681312). ClinVar contains an entry for this variant (Variation ID: 480547). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Human Genetics Bochum, Ruhr University Bochum	RCV001210928	SCV004704549	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2023-11-13	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PS1_MOD, PM1, PS4_SUP, PM2_SUP, PP3