Submissions for variant NM_004985.5(KRAS):c.451-5604T>C

dbSNP: rs397517476

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586927	SCV000527750	likely benign	not provided	2016-05-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844160	SCV000699774	likely benign	not specified	2022-02-27	criteria provided, single submitter	clinical testing	Variant summary: KRAS c.496T>C (p.Tyr166His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251188 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.496T>C has been reported in the literature as a VUS in a prenatal specimen tested for increased nuchal translucency at our laboratory (example, Leach_2019) and as an inherited benign variant from an asymptomatic father in an individual with a reported diagnosis of Noonan syndrome in whom a different pathogenic variant in the SOS1 gene was identified as the causative variant (example, Abe_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. The co-occurrence with another pathogenic variant(s) reported above (SOS1 c.925G>T, p.Asp309Tyr), provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003401425	SCV004104732	uncertain significance	KRAS-related condition	2023-03-31	criteria provided, single submitter	clinical testing	The KRAS c.496T>C variant is predicted to result in the amino acid substitution p.Tyr166His. This variant was reported with uncertain significance in a fetus with increased nuchal translucency from a prenatal cohort tested for Noonan syndrome (Supp Table S2, Leach NT et al. 2019. PubMed ID: 29907801). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-25368449-A-G), and has been classified as Likely Benign by two labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/386200). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.