KRAS NM_004985.4:c.178G>C, Gly60Arg

proposed classification - variant undergoing re-assessment, contact laboratory

The c.178G>C (p.Gly60Arg) variant in KRAS has been reported in the literature as a de novo occurrence in 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 16474404, 20949621). In vitro functional studies provide some evidence that the p.Gly60Arg variant may impact protein function (PS3; PMID 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in KRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of KRAS (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly60Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PS3, PM2, PM1, PP3, PP2.

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29493581). Missense variant. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20949621). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012586 /PMID: 16474404 /3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 16474404, 20949621). Different missense changes at the same codon (p.Gly60Ser, p.Gly60Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012597, VCV000163766 /PMID: 19396835). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 60 of the KRAS protein (p.Gly60Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 16474404, 26242988, 28650561). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12586). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt KRAS function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 20949621). For these reasons, this variant has been classified as Pathogenic.