ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.3G>T (p.Met1Ile) (rs769053886)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567881 SCV000663776 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000765375 SCV000896641 uncertain significance Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000587996 SCV000680957 uncertain significance not provided 2018-05-23 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.3G>T at the cDNA level and alters the initiator Methionine codon. 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. According to French et al. (2003), there is another Methionine 10 codons downstream that could potentially function as an initiation codon; therefore, it is possible that some functional protein is produced. RAD51C c.3G>T has been reported in at least one individual with breast cancer (Kraus 2017). This variant was not observed in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether RAD51C c.3G>T is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587996 SCV000699809 uncertain significance not provided 2017-05-08 criteria provided, single submitter clinical testing Variant summary: The RAD51C c.3G>T (p.Met1Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide that 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. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The human gene for RAD51C, has two potential start codons, 27 base pairs apart, neither of which is an ideal sequence context compared with the Kozak consensus (French_TheJofBioChem_2003). A functional study showed that a cDNA with a 5 truncation intended to delete the first ATG codon, resulted in a protein that maintained its ability to complement the mitomycin-C sensitivity to a very similar level to the WT in a RAD51C-deficient cell line through the use of the adjacent ATG downstream in the sequence (data not shown)(French_TheJofBioChem_2003). The variant of interest was absent in a large, broad control population, ExAC in 120822 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS, although a benign effect for this variant cannot be ruled out.
Invitae RCV000197479 SCV000255171 uncertain significance Fanconi anemia, complementation group O 2018-10-29 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the RAD51C mRNA. Because an alternate methionine that is highly conserved in mammalian species is only 9 codons downstream of this initiator methionine, it is uncertain if this variant results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual with breast cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 216798). Downstream of the known ATG start site, the nearest methionine codon that can be used to initiate translation of the RAD51C protein lies at codon 10. An experimental study has shown that the RAD51C protein created from this downstream methionine is biologically active, exhibiting wild-type activity in complementing mitomycin C sensitivity in a RAD51C-deficient cell line (PMID: 12966089). Based on these results, the impact of this variant on RAD51C protein function is uncertain. 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.

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