Submissions for variant NM_000249.4(MLH1):c.1081A>G (p.Lys361Glu)

dbSNP: rs786201875

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164376	SCV000215011	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-06	criteria provided, single submitter	clinical testing	The p.K361E variant (also known as c.1081A>G), located in coding exon 12 of the MLH1 gene, results from an A to G substitution at nucleotide position 1081. The lysine at codon 361 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well 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	RCV000629834	SCV000750790	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-17	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 185023). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs786201875, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 361 of the MLH1 protein (p.Lys361Glu).
Sema4, Sema4	RCV000164376	SCV002528620	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-12	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271435	SCV002556257	uncertain significance	not specified	2022-06-30	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1081A>G (p.Lys361Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250808 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1081A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory (MLH1 c.546-1G>A), providing supporting evidence for a benign role. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003995338	SCV004840951	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 361 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 1/250808 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.