rs199747712
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000251.3(MSH2):c.2777T>A(p.Ile926Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000807 in 1,611,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248580Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134472
GnomAD4 exome AF: 0.00000822 AC: 12AN: 1459590Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7AN XY: 725934
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74464
ClinVar
Submissions by phenotype
Lynch syndrome 1 Uncertain:3
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This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
not specified Uncertain:2
Variant summary: MSH2 c.2777T>A (p.Ile926Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248580 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2777T>A in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 237393). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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not provided Uncertain:2
This variant is denoted MSH2 c.2777T>A at the cDNA level, p.Ile926Asn (I926N) at the protein level, and results in the change of an Isoleucine to an Asparagine (ATC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile926Asn was not observed at a significant allele frequency in 1000 Genomes. Since Isoleucine and Asparagine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ile926Asn occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located within the helix-turn-helix domain and the MSH3 and MSH6 region of interaction (Guerrette 1998, Lützen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ile926Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
The MSH2 c.2777T>A (p.Ile926Asn) variant has been reported in the published literature in a cohort of individuals with colorectal adenocarcinoma (PMID: 32459922 (2020)), as well as in individuals with breast cancer and reportedly healthy individuals in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000027 (3/112578 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded inconclusive predictions. Based on the available information, we are unable to determine the clinical significance of this variant. -
Hereditary cancer-predisposing syndrome Uncertain:2
The p.I926N variant (also known as c.2777T>A), located in coding exon 16 of the MSH2 gene, results from a T to A substitution at nucleotide position 2777. The isoleucine at codon 926 is replaced by asparagine, an amino acid with dissimilar properties. This alteration was observed in the TCGA colorectal adenocarcinoma data set, which was used to represent sporadic cancer in a study of patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium (Lee YR et al. N Engl J Med, 2020 May;382:2103-2116). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
This missense variant replaces isoleucine with asparagine at codon 926 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/248580 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at