Submissions for variant NM_000249.4(MLH1):c.1670A>G (p.Glu557Gly)

gnomAD frequency: 0.00001  dbSNP: rs1235304501

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001012658	SCV001173139	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-20	criteria provided, single submitter	clinical testing	The p.E557G variant (also known as c.1670A>G), located in coding exon 15 of the MLH1 gene, results from an A to G substitution at nucleotide position 1670. The glutamic acid at codon 557 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well 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.
Invitae	RCV001051477	SCV001215632	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 557 of the MLH1 protein (p.Glu557Gly). 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: 819789). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV001012658	SCV001734366	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 557 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders 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	RCV004004514	SCV004843192	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 557 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders 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.