Submissions for variant NM_000249.4(MLH1):c.1118G>A (p.Gly373Glu)

gnomAD frequency: 0.00001  dbSNP: rs774878513

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204025	SCV000259769	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 373 of the MLH1 protein (p.Gly373Glu). This variant is present in population databases (rs774878513, gnomAD 0.002%). 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: 219728). 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 not expected to disrupt MLH1 protein function with a negative predictive value of 95%. 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	RCV000221361	SCV000275661	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	clinical testing	The p.G373E variant (also known as c.1118G>A), located in coding exon 12 of the MLH1 gene, results from a G to A substitution at nucleotide position 1118. The glycine at codon 373 is replaced by glutamic acid, an amino acid with 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.
Fulgent Genetics, Fulgent Genetics	RCV000764488	SCV000895559	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000221361	SCV000906867	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 373 in the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 2/251420 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.
GeneDx	RCV001355471	SCV001765871	uncertain significance	not provided	2022-08-15	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
All of Us Research Program, National Institutes of Health	RCV003997578	SCV004840957	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 373 in the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 2/251420 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355471	SCV001550364	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MLH1 p.Gly373Glu variant was not identified in the literature nor was it identified in the following databases: GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs774878513) as “With Uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae and Ambry Genetics). The variant was identified in control databases in 2 of 246214 chromosomes at a frequency of 0.000008 (Genome Aggregation Consortium Feb 27, 2017). The p.Gly373 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a significant difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.