rs63750465
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5PP3_Moderate
The NM_000249.4(MLH1):c.347C>A(p.Thr116Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,986 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T116P) has been classified as Pathogenic.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251410Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135874
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461808Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 727206
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74330
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2021 | Observed in individuals with MLH1-related cancers (Tournier 2008, Bouvet 2019); Published functional studies demonstrate no damaging effect: intact splicing and moderate cell survival after DNA damage (Tournier 2008, Bouvet 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22788692, 26333163, 22753075, 18561205, 12202775, 25871441, 23729658, 30998989) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 02, 2024 | The MLH1 c.347C>A (p.Thr116Lys) variant has been reported in the published literature in individuals affected with colorectal cancer (PMID: 18561205 (2008), 30998989 (2019)). Functional studies reported this variant had a neutral effect on MLH1 splicing (PMID: 18561205 (2008)) and protein function (PMID: 30998989 (2019)). The frequency of this variant in the general population, 0.000011 (3/282818 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2024 | The p.T116K variant (also known as c.347C>A), located in coding exon 4 of the MLH1 gene, results from a C to A substitution at nucleotide position 347. The threonine at codon 116 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in one individual either fulfilling Amsterdam II criteria or having a tumor demonstrating microsatellite instability (Tournier I et al. Hum Mutat, 2008 Dec;29:1412-24). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This variant has been identified in an individual diagnosed with colorectal cancer at 22 (Vibert R et al. Eur J Hum Genet, 2023 Sep;31:1078-1082). The T116K variant demonstrated evidence supporting benign in a methylation tolerance-based functional assay (Bouvet D et al. Gastroenterology, 2019 08;157:421-431). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 11, 2023 | This missense variant replaces threonine with lysine at codon 116 of the MLH1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown the mutant protein to exhibit normal function in a methylation tolerance-based functional assay (PMID: 30998989). This variant has been reported in an individual affected with or suspected of having Lynch syndrome (PMID: 18561205). This variant has been identified in 3/282818 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. - |
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 15, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 02, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 09, 2017 | Variant summary: The MLH1 c.347C>A (p.Thr116Lys) variant causes a missense change located in the Histidine kinase/HSP90-like ATPasedomain of the protein (InterPro) involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/277164 control chromosomes (gnomAD) at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). Tournier_2008 found this variant to have no effect on splicing in an ex vivo splicing assay. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS). - |
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 09, 2024 | This missense variant replaces threonine with lysine at codon 116 of the MLH1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown the mutant protein to exhibit normal function in a methylation tolerance-based functional assay (PMID: 30998989). This variant has been reported in an individual affected with or suspected of having Lynch syndrome (PMID: 18561205). This variant has been identified in 3/282818 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. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2025 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at