rs61752724
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_001040108.2(MLH3):āc.4097T>Cā(p.Ile1366Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1366V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001040108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH3 | NM_001040108.2 | c.4097T>C | p.Ile1366Thr | missense_variant | 12/13 | ENST00000355774.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.4097T>C | p.Ile1366Thr | missense_variant | 12/13 | 5 | NM_001040108.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152180Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251462Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135904
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461834Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727228
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152180Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 18, 2024 | The p.I1366T variant (also known as c.4097T>C), located in coding exon 11 of the MLH3 gene, results from a T to C substitution at nucleotide position 4097. The isoleucine at codon 1366 is replaced by threonine, an amino acid with similar properties. This amino acid position is 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 10, 2022 | 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 565365). This variant has not been reported in the literature in individuals affected with MLH3-related conditions. This variant is present in population databases (rs61752724, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1366 of the MLH3 protein (p.Ile1366Thr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at