chr2-47403351-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP3BP6
The NM_000251.3(MSH2):c.160G>T(p.Ala54Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000481 in 1,455,652 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A54T) has been classified as Uncertain significance.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.160G>T | p.Ala54Ser | missense_variant | 1/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.160G>T | p.Ala54Ser | missense_variant | 1/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000430 AC: 1AN: 232470Hom.: 0 AF XY: 0.00000786 AC XY: 1AN XY: 127236
GnomAD4 exome AF: 0.00000481 AC: 7AN: 1455652Hom.: 0 Cov.: 31 AF XY: 0.00000415 AC XY: 3AN XY: 723634
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 23, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 14, 2021 | Variant summary: MSH2 c.160G>T (p.Ala54Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 232470 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.160G>T in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 16, 2018 | The MSH2 c.160G>T; p.Ala54Ser variant (rs749212640) is reported as a variant of uncertain significance in the medical literature (DeRycke 2017). The variant is described as a variant of uncertain significance in the ClinVar database (Variation ID: 185536) the variant is found in the general population with an allele frequency of 0.0004% (1/228144 alleles) in the Genome Aggregation Database. The alanine at this position is highly conserved but computational analyses (SIFT: Tolerated, PolyPhen-2:Possibly Damaging) predict conflicting effects of this variant on protein structure/function. Based on available information, this variant is classified as a variant of uncertain significance. - |
Lynch syndrome 1 Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 17, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 03, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 14, 2024 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 23, 2023 | This missense variant replaces alanine with serine at codon 54 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 a cohort of individuals affected with Lynch syndrome-associated cancer (PMID: 36793599). This variant has been identified in 1/232470 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 | Oct 16, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27150160) - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at