ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.1A>T (p.Met1Leu) (rs561425038)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484387 SCV000567876 likely pathogenic not provided 2017-09-07 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. This variant has been reported in a BRCA1/2 negative woman with breast and ovarian cancer (Gutiérrez-Enríquez 2014). As RAD51D c.1A>T is predicted to alter normal protein production, it is considered a likely pathogenic variant.
Invitae RCV000558858 SCV000651721 uncertain significance Breast-ovarian cancer, familial 4 2019-01-02 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the RAD51D mRNA. The next in-frame methionine is located in exon 1 (p.Met16). This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast and ovarian cancer (PMID: 24130102). An experimental study has shown that RNA from the variant allele is expressed at equal levels as the wild-type allele, suggesting that the transcript does not undergo nonsense-mediated decay (PMID: 24130102). However, the effect of this variant on protein translation and function is unknown. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000558858 SCV000677793 likely pathogenic Breast-ovarian cancer, familial 4 2017-02-27 criteria provided, single submitter clinical testing
Color RCV000775946 SCV000910450 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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