Submissions for variant NM_000249.4(MLH1):c.563C>T (p.Ala188Val)

gnomAD frequency: 0.00001  dbSNP: rs777971431

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484514	SCV000568162	likely benign	not provided	2019-09-03	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000542526	SCV000625178	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 188 of the MLH1 protein (p.Ala188Val). This variant is present in population databases (rs777971431, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 419939). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV000574007	SCV000676038	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	The p.A188V variant (also known as c.563C>T), located in coding exon 7 of the MLH1 gene, results from a C to T substitution at nucleotide position 563. The alanine at codon 188 is replaced by valine, an amino acid with similar properties. This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health	RCV000574007	SCV000684843	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 188 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 not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 7/251302 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484514	SCV002047220	uncertain significance	not provided	2023-01-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00017 (6/34586 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021), LOVD https://databases.lovd.nl/shared/variants/MLH1). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV003476160	SCV004195032	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003315	SCV004835301	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 188 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 7/251302 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	RCV004526688	SCV005039773	uncertain significance	not specified	2024-03-19	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.563C>T (p.Ala188Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251302 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.563C>T has been reported in the literature in individuals affected with Lynch Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 419939). Based on the evidence outlined above, the variant was classified as uncertain significance.