Submissions for variant NM_002878.4(RAD51D):c.1A>T (p.Met1Leu)

dbSNP: rs561425038

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484387	SCV000567876	likely pathogenic	not provided	2020-05-05	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 24130102)
Invitae	RCV000558858	SCV000651721	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2022-10-03	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 and ovarian cancer (PMID: 24130102). ClinVar contains an entry for this variant (Variation ID: 419798). Studies have shown that disruption of the initiator codon does not significantly alter or has an unclear effect on RAD51D gene expression (PMID: 24130102). 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.
Counsyl	RCV000558858	SCV000677793	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2017-02-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775946	SCV000910450	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This variant results in the loss of the translation start codon (methionine at codon 1) 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 N-terminus (amino acids 1-83) of the RAD51D protein encodes the single-stranded DNA binding domain and that the 13-residue N-terminal tail (amino acids 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 function as an alternative translation initiation site and produce a functional RAD51D protein. This variant has been reported in an individual affected with breast and ovarian cancer (PMID: 24130102). A different nucleotide substitution (c.1A>G) with similar protein impact has also been reported in an individual affected with ovarian cancer (PMID: 26681312). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781803	SCV000920134	uncertain significance	not specified	2018-11-13	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.1A>T (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon (p.Met16). Two of four in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 241566 control chromosomes. Another start lost variant (c.1A>G) was found in 2/241566 control chromosomes in gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1A>T has been reported in the literature in one individual affected with Breast and Ovarian Cancer (Gutierrez-Enriquez_2014). As the family history information was not reported in the publication, these data do not allow any conclusion about variant significance. The same publication reports experimental evidence evaluating transcript expression of the mutant allele which showed levels equal to the wild-type in the cDNA sequence. Although this finding suggests no effect of this variant on nonsense-mediated decay and/or transcript expression, this assay is not quantitative, therefore does not allow convincing conclusions about the variant effect on either the translated protein product or its function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x pathogenic, 1x likely pathogenic, 1x VUS). Based on the evidence outlined above, the variant was classified as a VUS-possibly pathogenic variant until unequivocal co-segregation and functional evidence are obtained.
Ambry Genetics	RCV000775946	SCV002721815	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-14	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.1A>T) is located in coding exon 1 of the RAD51D gene and results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This alteration was identified in a female patient with breast cancer at 51 and ovarian cancer at 64 (Gutiérrez-Enríquez S et al. Int J Cancer, 2014 May;134:2088-97) and 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). A second in-frame methionine exists in RAD51D at amino acid position 16. However, this is predicted to be a relatively weak translation initiation site, and based on internal 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000484387	SCV004238611	likely pathogenic	not provided	2019-05-06	criteria provided, single submitter	clinical testing