Submissions for variant NM_000249.4(MLH1):c.1117G>A (p.Gly373Arg)

dbSNP: rs766904735

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166495	SCV000217294	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	The p.G373R variant (also known as c.1117G>A), located in coding exon 12 of the MLH1 gene, results from a G to A substitution at nucleotide position 1117. The glycine at codon 373 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole-genome sequencing and/or whole-exome sequencing; this patient was diagnosed with hypodiploid acute lymphocytic leukemia (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). 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.
Invitae	RCV000226857	SCV000284005	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 373 of the MLH1 protein (p.Gly373Arg). This variant is present in population databases (rs766904735, gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 186843). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein 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.
GeneDx	RCV000484742	SCV000569576	likely benign	not provided	2020-09-03	criteria provided, single submitter	clinical testing	Not observed 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; This variant is associated with the following publications: (PMID: 26580448)
Counsyl	RCV000662540	SCV000785117	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000708919	SCV000838009	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764487	SCV000895558	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	RCV000166495	SCV000904056	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 373 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 been reported in an individual affected with leukemia (PMID: 26580448). This variant has been identified in 1/246196 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800500	SCV002046933	uncertain significance	not specified	2021-04-19	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000764487	SCV002495845	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2021-05-03	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3 exon 12 p.Gly373Arg (c.1117G>A): This variant has been reported in the literature in one individual with ALL (Zhang 2015 PMID:26580448). This variant is not present in large control databases but is present in ClinVar (Variation ID:186843). Evolutionary conservation and computational predictive tools for this variant are unclear. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Myriad Genetics, Inc.	RCV000662540	SCV004018124	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662540	SCV004192978	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-06-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708919	SCV004840956	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 373 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 been reported in an individual affected with leukemia (PMID: 26580448). This variant has been identified in 1/246196 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.