Submissions for variant NM_000249.4(MLH1):c.2060G>A (p.Arg687Gln)

gnomAD frequency: 0.00001  dbSNP: rs587781310

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129035	SCV000172945	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-18	criteria provided, single submitter	clinical testing	The p.R687Q variant (also known as c.2060G>A), located in coding exon 18 of the MLH1 gene, results from a G to A substitution at nucleotide position 2060. The arginine at codon 687 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in a 46-year-old male diagnosed with colorectal cancer (Xu Y et al. Front Genet. 2020 Aug;11:991). 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.
Invitae	RCV000168237	SCV000218906	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 687 of the MLH1 protein (p.Arg687Gln). This variant is present in population databases (rs587781310, gnomAD 0.01%). 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: 140838). 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%. This variant disrupts the p.Arg687 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11139242, 11748856, 11920650, 14762794, 17510385, 19697156, 21404117, 24440087, 26485756). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health	RCV000129035	SCV001346832	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 687 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 colorectal cancer (PMID: 32973888). This variant has been identified in 3/251180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2059C>T (p.Arg687Trp), is considered to be disease-causing (ClinVar variation ID: 90014), suggesting that this position is important for the protein function. 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	RCV001578234	SCV001805785	uncertain significance	not provided	2019-10-18	criteria provided, single submitter	clinical testing	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
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291567	SCV002584722	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2022-07-11	criteria provided, single submitter	clinical testing	The MLH1 c.2060G>A (p.Arg687Gln) missense change has a maximum subpopulation frequency of 0.014% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 32973888, 33672345). Another missense variant at the same amino acid residue, Arg687Trp, has been reported in individuals with Lynch syndrome and has been determined to be pathogenic by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV002291567	SCV004195062	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997473	SCV004843264	uncertain significance	Lynch syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 687 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 hereditary cancer in the literature. This variant has been identified in 3/251180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2059C>T (p.Arg687Trp), is considered to be disease-causing (ClinVar variation ID: 90014), suggesting that this position is important for the protein function. 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.