Submissions for variant NM_000249.4(MLH1):c.539T>G (p.Val180Gly)

gnomAD frequency: 0.00003  dbSNP: rs63750102

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131749	SCV000186791	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	The p.V180G variant (also known as c.539T>G), located in coding exon 6 of the MLH1 gene, results from a T to G substitution at nucleotide position 539. The valine at codon 180 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in one individual with MSI-L endometrial cancer with absent MLH1 on IHC and one individual with pancreatic cancer (Berends MJ et al. J. Clin. Oncol. 2003 Dec;21:4364-70; Shindo K et al. J. Clin. Oncol. 2017 Oct;35(30):3382-3390)). In addition, p.V180G was detected in the Danish HNPCC registry in conjunction with a pathogenic MSH2 mutation in an individual with glioblastoma (Therkildsen C et al. Eur. J. Neurol. 2015 Apr;22(4):717-24). This alteration has been classified as a variant of unknown significance using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). 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.
GeneDx	RCV000212519	SCV000211089	uncertain significance	not provided	2023-05-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including endometrial, colorectal, pancreatic, and other cancers (Berends et al., 2003; Nilbert et al., 2009; Therkildsen et al., 2015; Shindo et al., 2017; Hu et al., 2020); Published functional studies demonstrate intermediate effects on microsatellite instability and mutation accumulation (Houlleberghs et al., 2020); This variant is associated with the following publications: (PMID: 18566915, 14645426, 25648859, 26333163, 17192056, 28767289, 31391288, 32659497, 22753075, 36461907, 31784484)
Invitae	RCV000524305	SCV000284065	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 180 of the MLH1 protein (p.Val180Gly). This variant is present in population databases (rs63750102, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 14645426, 18566915, 25648859, 28767289). ClinVar contains an entry for this variant (Variation ID: 90257). 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 expected to disrupt MLH1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 31784484). 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.
Counsyl	RCV000411648	SCV000489405	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-09-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131749	SCV000684838	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 180 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 reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 18566915, 25648859), endometrial cancer (PMID: 14645426), breast/ovarian cancer (PMID: 34359559), or pancreatic cancer (PMID: 28767289). This variant has been identified in 11/251434 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	RCV000212519	SCV001134315	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000079 (9/113724 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with suspected Lynch syndrome (PMID: 18566915 (2009), 25648859 (2015)), endometrial cancer (PMID: 14645426 (2003)) and pancreatic cancer (PMID: 28767289 (2017)). Published functional studies found this variant to have an intermediate effect on attenuating mismatch repair (MMR) function (PMID: 31784484 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
CeGaT Center for Human Genetics Tuebingen	RCV000212519	SCV001153835	uncertain significance	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000411648	SCV001310313	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000411648	SCV001481615	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2020-10-15	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Myriad Genetics, Inc.	RCV000411648	SCV004018187	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320556	SCV004024894	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997133	SCV004835297	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 180 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 reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 18566915, 25648859), endometrial cancer (PMID: 14645426), breast/ovarian cancer (PMID: 34359559), or pancreatic cancer (PMID: 28767289). This variant has been identified in 11/251434 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.