Submissions for variant NM_000249.4(MLH1):c.1569G>T (p.Glu523Asp)

dbSNP: rs63751680

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552506	SCV000625081	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 523 of the MLH1 protein (p.Glu523Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 28449805). ClinVar contains an entry for this variant (Variation ID: 89792). 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: 17510385, 30998989). 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	RCV000562703	SCV000669517	likely benign	Hereditary cancer-predisposing syndrome	2016-06-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589315	SCV000696117	uncertain significance	not provided	2017-05-18	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1569G>T (p.Glu523Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Two functional studies showed that the mutation is not localized in, and does not create or disrupt any regulatory sequence (Lastella_BMC Genomics_2006) and that this variant maintained 76.6% in vitro MMR activity with >75% relative MLH1 expression (Takahashi_Cancer Res_2007). The neutrality of this variant has been suggested by computational studies (Chao_MSH2-MLH1_HM_2008, Lastella_BMC Genomics_2006). The variant of interest has not been found in a large, broad control population, ExAC in 121250 control chromosomes. One reputable database classified this variant as uncertain significance. The variant is classified as VUS until more functional studies and/or clinical information become available.
Color Diagnostics, LLC DBA Color Health	RCV000562703	SCV000908636	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000589315	SCV000977383	likely benign	not provided	2018-04-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.