rs377433038
Variant summary
Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4
This summary comes from the ClinGen Evidence Repository: The NM_000249.4: c.1270G>A variant in MLH1 is a missense variant predicted to cause substitution of Alanin by Threonin at amino acid 424 (p.Ala424Thr). The prior probability of this variant is 0,10 which fullfills the criteria of BP4 (missense variant with MAPP+PolyPhen-2 prior probability for pathogenicity <0.11 as per http://priors.hci.utah.edu/PRIORS). The Frequency of this variant in gnomAD V4.1.0 Grpmax AF = 0.00005797 (0.005797%), which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (<1 in 50,000 alleles) for PM2_supporting, and therefore PM2_supporting is not met.Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PM2_SUP, BP4 (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA028060/MONDO:0012249/115
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Uncertain_significance. The variant received -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152052Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 251328 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000575 AC: 84AN: 1461888Hom.: 0 Cov.: 34 AF XY: 0.0000578 AC XY: 42AN XY: 727244 show subpopulations
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152052Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74242 show subpopulations
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:2Benign:1
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: 27363726]. -
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not specified Uncertain:2
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Variant summary: MLH1 c.1270G>A (p.Ala424Thr) results in a non-conservative amino acid change in 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 5.5e-05 in 1613940 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MLH1 causing Lynch Syndrome (5.5e-05 vs 0.00071), allowing no conclusion about variant significance. c.1270G>A has been reported in the literature in individuals with a family history of cancer (deOliveira_2022) and inflammatory bowel disease-associated colorectal cancers (Din_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29950348, 35534704). ClinVar contains an entry for this variant (Variation ID: 220203). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:2
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In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25111426, Plazzer2024[preprint], 35534704, 22753075) -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This missense variant replaces alanine with threonine at codon 424 of the MLH1 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 been reported in an individual affected with colorectal cancer (PMID: 29950348). This variant has been identified in 8/282614 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. -
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
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Lynch syndrome Benign:1
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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