ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.157G>A (p.Glu53Lys)

gnomAD frequency: 0.00001  dbSNP: rs63751199
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219506 SCV000279533 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.157G>A at the cDNA level, p.Glu53Lys (E53K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MLH1 Glu53Lys was not observed in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Glu53Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000581145 SCV000684757 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-27 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 53 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 MLH1-associated disease 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000701302 SCV000830095 benign Hereditary nonpolyposis colorectal neoplasms 2024-09-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000581145 SCV002703383 uncertain significance Hereditary cancer-predisposing syndrome 2024-09-23 criteria provided, single submitter clinical testing The p.E53K variant (also known as c.157G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at nucleotide position 157. The glutamic acid at codon 53 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health RCV003998631 SCV004835241 uncertain significance Lynch syndrome 2024-04-10 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 53 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 MLH1-associated disease 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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