Submissions for variant NM_000249.4(MLH1):c.2159T>G (p.Val720Gly)

dbSNP: rs587778985

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162502	SCV000212891	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	The p.V720G variant (also known as c.2159T>G), located in coding exon 19 of the MLH1 gene, results from a T to G substitution at nucleotide position 2159. The valine at codon 720 is replaced by glycine, an amino acid with dissimilar properties. This alteration was observed in a 60 year old male with Lynch-like syndrome (LLS) in a cohort of 81 patients with LLS and 47 patients with Lynch syndrome who all had mismatch repair deficient colorectal cancer (Xu Y et al. Front Genet, 2020 Aug;11:991). In a study that quantified tumor characteristics to assess pathogenicity for germline mismatch repair gene variants, this variant was reported in individuals whose Lynch syndrome-associated tumor demonstrated loss of MLH1 and/or PMS2 expression on immunohistochemistry, a subset also confirmed to be BRAF wild-type and /or absent for MLH1 promoter hypermethylation (Ambry internal data; Li S et al. J. Med. Genet. 2020 Jan;57:62-69). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000627729	SCV000543605	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-07	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 90076). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 720 of the MLH1 protein (p.Val720Gly).
Color Diagnostics, LLC DBA Color Health	RCV000162502	SCV001339539	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-29	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 720 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 32973888; ClinVar SCV000212891.6) and in two individuals affected with unspecified cancers (PMID: 31391288). 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.
Sema4, Sema4	RCV000162502	SCV002528722	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-16	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288571	SCV002581460	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2022-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002288571	SCV004190650	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-08-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997124	SCV004843288	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 720 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 32973888; ClinVar SCV000212891.6) and in two individuals affected with unspecified cancers (PMID: 31391288). 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.