2-47463052-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate
The NM_000251.3(MSH2):c.1408G>C(p.Val470Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V470E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MSH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 470 of the MSH2 protein (p.Val470Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. -
Hereditary cancer-predisposing syndrome Uncertain:1
PM2_Supporting, BS3 c.1408G>C, located in exon 9 of the MSH2 gene, is predicted to result in the substitution of Val by Leu at codon 470, p.(Val470Leu).It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). Computational tools for this variant suggests no significant impact on splicing but the effect of the variant on protein function is indeterminate (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.18). A functional study based on cell viability assay in HEK293 or HAP1 cells using 6-TG treatment demonstrates normal function for this variant, with a LOF score -2,04 (PMID 33357406) (BS3).To our knowledge, relevant clinical data has not been reported for this variant. This variant has been reported in the ClinVar database (1x uncertain significance), but it has not been reported neither in InSiGHT nor in LOVD databases. Based on currently available information, the variant c.1408G>C should be considered an uncertain significance variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at