Submissions for variant NM_000249.4(MLH1):c.69A>T (p.Glu23Asp)

dbSNP: rs63750555

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411283	SCV000489685	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001025892	SCV001188169	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	clinical testing	The p.E23D variant (also known as c.69A>T), located in coding exon 1 of the MLH1 gene, results from an A to T substitution at nucleotide position 69. The glutamic acid at codon 23 is replaced by aspartic acid, an amino acid with highly similar properties. A functional study showed only 25% MMR activity in yeast with the p.E23D variant; however, immunohistochemistry analyses (IHC) indicated >75% expression when compared to wild type. These findings suggest that loss of MLH1 expression may not be detected by IHC in those with p.E23D (Takahashi et al. Cancer Res. 2007 May 15;67(10):4595-604). In another functional study, this variant demonstrated a mutator phenotype in a yeast reversion assay (Wanat JJ et al. Hum. Mol. Genet. 2007 Feb;16:445-52). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MLH1-related disease (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001236964	SCV001409707	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-12-05	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 23 of the MLH1 protein (p.Glu23Asp). 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: 90335). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MLH1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 17210669, 17510385). 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.
Color Diagnostics, LLC DBA Color Health	RCV001025892	SCV002052119	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 23 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the equivalent yeast variant had a mutator phenotype (PMID: 17210669), and that this variant had 25.2% mismatch repair activity in a yeast-based assay (PMID: 17510385). To our knowledge, 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.
All of Us Research Program, National Institutes of Health	RCV003997137	SCV004835229	uncertain significance	Lynch syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 23 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the equivalent yeast variant had a mutator phenotype (PMID: 17210669), and that this variant had 25.2% mismatch repair activity in a yeast-based assay (PMID: 17510385). To our knowledge, 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.