rs371667663
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM5BP4
The NM_000249.4(MLH1):āc.343A>Gā(p.Ile115Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. I115N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.343A>G | p.Ile115Val | missense_variant | 4/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.343A>G | p.Ile115Val | missense_variant | 4/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251412Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135876
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461842Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 727218
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 15, 2023 | The p.I115V variant (also known as c.343A>G), located in coding exon 4 of the MLH1 gene, results from an A to G substitution at nucleotide position 343. The isoleucine at codon 115 is replaced by valine, an amino acid with highly similar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 27, 2023 | This missense variant replaces isoleucine with valine at codon 115 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual with clinical features of Lynch Syndrome (ClinVar SCV000625151.7). This variant has been identified in 2/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 05, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2022 | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075) - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 115 of the MLH1 protein (p.Ile115Val). This variant is present in population databases (rs371667663, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 455430). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at