Submissions for variant NM_002878.4(RAD51D):c.2T>A (p.Met1Lys)

dbSNP: rs1064794619

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522287	SCV000618339	likely pathogenic	not provided	2017-03-17	criteria provided, single submitter	clinical testing	This variant alters the initiator Methionine codon, and the resultant protein would be described as “p.Met1?” to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. RAD51D c.2T>A has not been previously published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, the adjacent variant RAD51D c.1A>T, which also results in p.Met1?, has been reported in an individual with a personal history of both breast and ovarian cancer (Gutierrez-Enriquez 2014). As RAD51D c.2T>A is predicted to alter normal protein production, it is considered to be a likely pathogenic variant.
Color Diagnostics, LLC DBA Color Health	RCV001805135	SCV002052871	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-03-10	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 (amino acid 1-83) encodes the single-stranded DNA binding domain and that the 13-residue N-terminal tail (amino acid 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. However, different variants (c.1A>G, c.1A>T) that also disrupt p.Met1 have been reported in individuals affected with ovarian cancer (ClinVar variation ID: 127884, 419798). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV001805135	SCV002747934	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-04-25	criteria provided, single submitter	clinical testing	The p.M1? variant (also known as c.2T>A) is located in coding exon 1 of the RAD51D gene and results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This variant was identified in a cohort of 4439 women with ovarian cancer undergoing multigene panel testing at one laboratory (Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488). This amino acid position is highly conserved in available vertebrate species. 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 majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005091213	SCV005832098	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-09-09	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 not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with breast cancer, colon polyps, and/or ovarian cancer (PMID: 24130102, 26681312, 30322717, 33047316). ClinVar contains an entry for this variant (Variation ID: 449883). 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.