rs754824872
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000251.3(MSH2):c.2072T>C(p.Ile691Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,884 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 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251474Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727240
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 14, 2023 | This missense variant replaces isoleucine with threonine at codon 691 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 21671081) and colorectal cancer (PMID: 11606497, 31428572). This variant has been identified in 1/251474 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 28, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 21, 2021 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This missense variant replaces isoleucine with threonine at codon 691 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 21671081) and colorectal cancer (PMID: 11606497, 31428572). This variant has been identified in 1/251474 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 06, 2022 | Observed in individuals with a personal history of colorectal cancer, with at least some tumors demonstrating microsatellite instability and/or loss of MSH2 protein expression, but all of whom also harbored a second MSH2 variant (Samowitz et al., 2001; Kovac et al., 2011; Zhunussova et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31428572, 11606497, 21671081, 18822302, 21120944) - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 10, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 691 of the MSH2 protein (p.Ile691Thr). This variant is present in population databases (rs754824872, gnomAD 0.0009%). This missense change has been observed in individual(s) with colon cancer (PMID: 11606497, 21671081). ClinVar contains an entry for this variant (Variation ID: 216349). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. 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. - |
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at