2-47416351-G-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000251.3(MSH2):c.998G>T(p.Cys333Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C333R) has been classified as Pathogenic.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Lynch syndrome 1 Pathogenic:2
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data]. -
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Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 333 of the MSH2 protein (p.Cys333Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 638846). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. This variant disrupts the p.Cys333 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12624141, 15849733, 16175654, 21642682, 28769567, 25559809, 26681312, 18951462, 17101317, 26951660, 17720936). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.C333F variant (also known as c.998G>T), located in coding exon 6 of the MSH2 gene, results from a G to T substitution at nucleotide position 998. The cysteine at codon 333 is replaced by phenylalanine, an amino acid with highly dissimilar properties. A likely pathogenic variant (p.C333R) and a pathogenic mutation (p.C333Y) have been been described at the same codon, and both have been identified in individuals meeting Amsterdam criteria with tumors demonstrating absent MSH2 and MSH6 by IHC (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at