Submissions for variant NM_000249.4(MLH1):c.174G>T (p.Leu58Phe)

dbSNP: rs762162504

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001058414	SCV001222980	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-01-10	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 58 of the MLH1 protein (p.Leu58Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine.
Color Diagnostics, LLC DBA Color Health	RCV001176034	SCV001339849	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-13	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 58 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. 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.
Ambry Genetics	RCV001176034	SCV002711637	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-17	criteria provided, single submitter	clinical testing	The p.L58F variant (also known as c.174G>T), located in coding exon 2 of the MLH1 gene, results from a G to T substitution at nucleotide position 174. The leucine at codon 58 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly 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.
All of Us Research Program, National Institutes of Health	RCV004000102	SCV004835244	uncertain significance	Lynch syndrome	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 58 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. 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.