ClinVar Genomic variation as it relates to human health

This sequence change affects the initiator methionine of the RAD51C mRNA. The next in-frame methionine is located at codon 10. 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 (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 216798). 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.

The p.M1? variant (also known as c.3G>T) is located in coding exon 1 of the RAD51C gene and results from a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. This alteration was reported as a variant of unknown significance in a woman with breast cancer diagnosed at age 67 from a cohort of 581 German high risk breast/ovarian cancer patients (Kraus C et al. Int. J. Cancer 2017 Jan;140(1):95-102). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 9 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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.

Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which a downstream in-frame ATG could serve as an alternate initiator codon, with published functional studies reporting the shortened product to retain wild-type function (French et al., 2003); Observed in an individual with breast cancer (Kraus et al., 2017); This variant is associated with the following publications: (PMID: 14704354, 22167183, 12966089, 25292178, 27616075)

This variant affects the translation start codon of the RAD51C gene and may result in an absent or non-functional protein product. However, an in-frame methionine 9 codons downstream may function as an alternative start codon and is located before the first known functional domain (RAD51B/RAD51D/XRCC3 interacting domain at amino acids 79-136) of the RAD51C protein. A functional study has shown that the RAD51C protein produced from this downstream methionine can function similarly to the wild type protein (PMID: 12966089). This variant has been reported in an individual affected with breast cancer (PMID: 27616075). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.