Submissions for variant NM_000249.4(MLH1):c.532G>C (p.Glu178Gln)

gnomAD frequency: 0.00001  dbSNP: rs1248251121

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797393	SCV000936947	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 178 of the MLH1 protein (p.Glu178Gln). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 643641). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 function. 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.
Ambry Genetics	RCV001023940	SCV001185884	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-18	criteria provided, single submitter	clinical testing	The p.E178Q variant (also known as c.532G>C), located in coding exon 6 of the MLH1 gene, results from a G to C substitution at nucleotide position 532. The glutamic acid at codon 178 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is 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.
GeneDx	RCV001772054	SCV001993386	uncertain significance	not provided	2019-08-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003472352	SCV004195026	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004807180	SCV005427843	uncertain significance	Lynch syndrome	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 178 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-related disorders in the literature. This variant has been identified in 2/251434 chromosomes 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.
Fulgent Genetics, Fulgent Genetics	RCV005036148	SCV005662496	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2024-01-11	criteria provided, single submitter	clinical testing