rs267607707
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000249.4(MLH1):c.107T>A(p.Ile36Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. I36M) has been classified as Uncertain significance.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.107T>A | p.Ile36Asn | missense_variant | 1/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.107T>A | p.Ile36Asn | missense_variant | 1/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 05, 2020 | The p.I36N variant (also known as c.107T>A), located in coding exon 1 of the MLH1 gene, results from a T to A substitution at nucleotide position 107. The isoleucine at codon 36 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been identified as somatic in conjunction with copy neutral loss of heterozygosity (CN-LOH) in a MSI-H colon tumor with loss of MLH1 on IHC where MLH1 promotor hypermethylation was negative (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5). This alteration has also been identified in the germline of a Chinese proband suspected to have Lynch syndrome (Sheng JQ et al. Cytogenet. Genome Res. 2008;122(1):22-7). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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