rs776174711
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_000251.3(MSH2):c.1130A>G(p.Gln377Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251420Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135902
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461834Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727220
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74354
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. -
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not specified Uncertain:2
Variant summary: MSH2 c.1130A>G (p.Gln377Arg) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246238 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.1130A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four 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. -
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1130A>G, in exon 7 that results in an amino acid change, p.Gln377Arg. This sequence change has been described in gnomAD with a frequency of 0.0029% in the Latino sub-population (dbSNP rs776174711). The p.Gln377Arg change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gln377Arg substitution. This sequence change does not appear to have been previously described in patients with MSH2-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Gln377Arg change remains unknown at this time. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This missense variant replaces glutamine with arginine at codon 377 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). 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 an individual suspected of having Lynch syndrome (Alvarez 2011 thesis, U. de Salamanca) and in individuals affected with breast/ovarian cancer (DOI: 10.1101/2021.04.15.21255554v2; Guardiola 2019 thesis, Univ. de Murcia; PMID: 33606809). This variant has been identified in 1/251420 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. -
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. -
Lynch syndrome Uncertain:1
This missense variant replaces glutamine with arginine at codon 377 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). Functional studies have shown that cells expressing this variant responded normally to the anti-metabolite 6-thioguanine (PMID: 33357406). This variant has been reported in an individual suspected of having Lynch syndrome (Alvarez 2011 thesis, U. de Salamanca) and in individuals affected with breast/ovarian cancer (DOI: 10.1101/2021.04.15.21255554v2; Guardiola 2019 thesis, Univ. de Murcia; PMID: 33606809). This variant has been identified in 1/251420 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
Published functional studies demonstrate no damaging effect: exhibits sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type (PMID: 33357406); 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: 35245693, 33357406, 36550560, 35264596, 33606809, 35534704, 18822302, 21120944) -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Hereditary cancer Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at