Submissions for variant NM_000249.4(MLH1):c.400A>G (p.Lys134Glu)

dbSNP: rs1060500710

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000461241	SCV000543645	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 134 of the MLH1 protein (p.Lys134Glu). This variant is present in population databases (no rsID available, 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: 405430). 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%. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 17135187). 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	RCV000562753	SCV000662107	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-26	criteria provided, single submitter	clinical testing	The p.K134E variant (also known as c.400A>G), located in coding exon 5 of the MLH1 gene, results from an A to G substitution at nucleotide position 400. The lysine at codon 134 is replaced by glutamic acid, an amino acid with similar properties. In one study, an in vitro mismatch repair assay concluded this alteration does not significantly impair the mismatch repair ability of MutLα, the MLH1-PMS2 heterodimer (Plotz G et al. Nucleic Acids Res., 2006 Nov;34:6574-86). In another study, this variant was reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
GeneDx	RCV001552099	SCV001772734	uncertain significance	not provided	2023-06-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate mismatch repair activity close to wild type (Plotz et al., 2006); Not observed in any cases, but was observed in unaffected controls from a breast cancer study (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 24362816, 22753075, 36909643, 17135187, 33471991)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001552099	SCV002009361	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000663	SCV004841234	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing