Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000249.4(MLH1):c.1270G>A(p.Ala424Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. A424G) has been classified as Uncertain significance.
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
Verdict is Likely_benign. Variant got -3 ACMG points.
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.088508844).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 3-37025868-G-A is Benign according to our data. Variant chr3-37025868-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220203.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}.
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:2
Uncertain significance, criteria provided, single submitter
clinical testing
Mendelics
May 28, 2019
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Baylor Genetics
Aug 21, 2023
- -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter
clinical testing
Mayo Clinic Laboratories, Mayo Clinic
Feb 22, 2022
- -
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Dec 01, 2020
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 25111426) -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 03, 2022
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. -
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Dec 14, 2015
- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Jan 29, 2024
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 424 of the MLH1 protein (p.Ala424Thr). This variant is present in population databases (rs377433038, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 220203). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. 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. -
Lynch syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health