rs1060500704
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000249.4(MLH1):c.1026G>A(p.Met342Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M342R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000249.4 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 |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1026G>A | p.Met342Ile | missense_variant | 11/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1026G>A | p.Met342Ile | missense_variant | 11/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 14, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 12, 2016 | This sequence change replaces methionine with isoleucine at codon 342 of the MLH1 protein (p.Met342Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MLH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 18, 2021 | The p.M342I variant (also known as c.1026G>A), located in coding exon 11 of the MLH1 gene, results from a G to A substitution at nucleotide position 1026. The methionine at codon 342 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at