Submissions for variant NM_000249.4(MLH1):c.37G>C (p.Glu13Gln)

dbSNP: rs587779008

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563924	SCV000676039	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-29	criteria provided, single submitter	clinical testing	The p.E13Q variant (also known as c.37G>C), located in coding exon 1 of the MLH1 gene, results from a G to C substitution at nucleotide position 37. The glutamic acid at codon 13 is replaced by glutamine, an amino acid with highly similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV000563924	SCV000684825	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 13 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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	RCV001251349	SCV001426917	uncertain significance	not specified	2020-07-16	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.37G>C (p.Glu13Gln) results in a conservative amino acid change of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 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.37G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001301371	SCV001490538	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-05-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 13 of the MLH1 protein (p.Glu13Gln). This variant is not present in population databases (gnomAD no frequency). 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: 486850). 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 with a negative predictive value of 95%. 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.
Baylor Genetics	RCV003465280	SCV004192964	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-23	criteria provided, single submitter	clinical testing
GeneDx	RCV004592780	SCV005080793	uncertain significance	not provided	2024-04-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075)