Submissions for variant NM_000249.4(MLH1):c.1850A>C (p.Lys617Thr)

gnomAD frequency: 0.00001  dbSNP: rs780199021

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196169	SCV000254360	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 617 of the MLH1 protein (p.Lys617Thr). This variant is present in population databases (rs780199021, gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28449805). ClinVar contains an entry for this variant (Variation ID: 216334). 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. 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.
Ambry Genetics	RCV000234867	SCV000276966	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-18	criteria provided, single submitter	clinical testing	The c.1850A>C (p.K617T) alteration is located in exon 16 (coding exon 16) of the MLH1 gene. This alteration results from a A to C substitution at nucleotide position 1850, causing the lysine (K) at amino acid position 617 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000234867	SCV000292195	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 617 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer and Lynch syndrome (PMID: 28449805, 28135145). This variant has been identified in 2/251420 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586570	SCV000696130	uncertain significance	not provided	2017-03-30	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1850A>C (p.Lys617Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 1/121402 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Sema4, Sema4	RCV000234867	SCV002528684	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	curation
Baylor Genetics	RCV003468906	SCV004195053	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586570	SCV004220856	uncertain significance	not provided	2023-06-30	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with colorectal cancer (PMID: 28135145 (2017)), and in at least one individual suspected of having Lynch syndrome (PMID: 28449805 (2017)). The frequency of this variant in the general population, 0.000008 (2/251420 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 conflicting predictions that this variant is deleterious or benign. 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	RCV003997009	SCV004843224	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 617 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 28449805) and breast cancer (DOI: 10.1101/2021.04.15.21255554). This variant has been identified in 2/251420 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.