3-37020342-A-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000249.4(MLH1):c.917A>T(p.Asn306Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. N306K) has been classified as Pathogenic.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.917A>T | p.Asn306Ile | missense_variant | 11/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.917A>T | p.Asn306Ile | missense_variant | 11/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251432Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135886
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727244
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 12, 2022 | The p.N306I variant (also known as c.917A>T), located in coding exon 11 of the MLH1 gene, results from an A to T substitution at nucleotide position 917. The asparagine at codon 306 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration has been reported in a cohort of high risk breast and ovarian cancer patients (Castéra L et al, Eur. J. Hum. Genet. 2014 Nov; 22(11):1305-1). This amino acid position is highly 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 | Color Diagnostics, LLC DBA Color Health | Jul 30, 2018 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 31, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2021 | Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with a personal and/or family history of breast and/or ovarian cancer (Castera 2014); This variant is associated with the following publications: (PMID: 22753075, 24549055) - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 306 of the MLH1 protein (p.Asn306Ile). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 24549055). ClinVar contains an entry for this variant (Variation ID: 231940). 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 expected to disrupt MLH1 protein function with a positive 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at