Submissions for variant NM_000249.4(MLH1):c.347C>A (p.Thr116Lys)

gnomAD frequency: 0.00004  dbSNP: rs63750465

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235173	SCV000149390	uncertain significance	not provided	2021-09-20	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV000115481	SCV000186795	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-06	criteria provided, single submitter	clinical testing	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). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000524292	SCV000261100	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 116 of the MLH1 protein (p.Thr116Lys). This variant is present in population databases (rs63750465, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer, Lynch syndrome, and reported in Universal Mutation Database (PMID: 18561205, 23729658, 30998989). ClinVar contains an entry for this variant (Variation ID: 90176). 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 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 30998989). 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.
Counsyl	RCV000410226	SCV000489667	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115481	SCV000684819	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000764481	SCV000895552	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780414	SCV000917641	uncertain significance	not specified	2017-11-09	criteria provided, single submitter	clinical testing	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).
Myriad Genetics, Inc.	RCV000410226	SCV004018191	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	criteria provided, single submitter	clinical testing	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].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235173	SCV004220885	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with hereditary nonpolyposis colorectal cancer (HNPCC) (Lynch Syndrome) (PMID: 18561205 (2008)), and colorectal cancer (PMID: 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.
All of Us Research Program, National Institutes of Health	RCV003997128	SCV004835269	uncertain significance	Lynch syndrome	2024-01-10	criteria provided, single submitter	clinical testing	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.