Submissions for variant NM_000249.4(MLH1):c.1051G>A (p.Gly351Arg)

gnomAD frequency: 0.00003  dbSNP: rs1437454428

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000629849	SCV000750805	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985774	SCV001134284	uncertain significance	not provided	2019-03-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001017137	SCV001178170	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-23	criteria provided, single submitter	clinical testing	The p.G351R variant (also known as c.1051G>A), located in coding exon 12 of the MLH1 gene, results from a G to A substitution at nucleotide position 1051. The glycine at codon 351 is replaced by arginine, an amino acid with dissimilar 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.
Color Diagnostics, LLC DBA Color Health	RCV001017137	SCV001346527	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 351 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 performed 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.
Fulgent Genetics, Fulgent Genetics	RCV002492942	SCV002777187	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2021-08-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003459491	SCV004192970	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002777	SCV004840941	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 351 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 been identified in an individual affected with colorectal and endometrial cancer (Color internal data). 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.