KRAS p.Pro34Leu

The c.101C>T variant in the KRAS gene is a missense variant predicted to cause substitution of proline by leucine at amino acid 34 (p.Pro34Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.867 supporting a deleterious impact to KRAS function (PP3). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). A different pathogenic missense variant has been previously identified at this codon of KRAS (c.101C>G (p.Pro34Arg)) which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 12590). This variant has been reported in 3 individuals as two confirmed de novo occurrences and one unconfirmed de novo occurrence with clinical features of a RASopathy (PS4_Moderate, PS2_VeryStrong; PMIDs: 17056636, 30732632, ClinVar SCV: SCV000207884.10, Internal lab contributors: GeneDx). A RAS activation assay showed that this variant led to increased RAS activation (PS3_Supporting; PMID: 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4_Moderate, PM5, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 09/17/2024)