ClinVar Miner

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

dbSNP: rs63750555
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Total submissions: 5
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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.
Invitae RCV001236964 SCV001409707 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-01-03 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. Experimental studies have shown that this missense change affects MLH1 function (PMID: 17210669, 17510385). 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 expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 90335). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). 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).
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.

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