Submissions for variant NM_000249.4(MLH1):c.1360G>C (p.Gly454Arg)

gnomAD frequency: 0.00006  dbSNP: rs63750527

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587838	SCV000149367	likely benign	not provided	2021-09-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30998989, 28874130, 25929848, 27150160, 12624141, 18383312, 22290698, 16395668, 25133505, 21404117, 31159747)
Invitae	RCV001080105	SCV000166244	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115458	SCV000184486	likely benign	Hereditary cancer-predisposing syndrome	2018-08-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000410484	SCV000487861	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2015-11-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000200984	SCV000539644	uncertain significance	not specified	2016-03-31	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD; ExAC: 6/16506 South Asian; ClinVar: 4 VUS (1 expert panel)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587838	SCV000601352	likely benign	not provided	2019-11-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200984	SCV000696108	benign	not specified	2022-05-14	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1360G>C (p.Gly454Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250988 control chromosomes (gnomAD). This frequency is not higher than the expected maximum for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.00012 vs 0.00071), allowing no conclusion about variant significance. The variant, c.1360G>C, has been reported in the literature in individuals affected with tumors that belong to the Lynch syndrome tumor spectrum (e.g. Parc_2003, Auclair_2006, Hardt_2011, Loizidou_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variants have been reported (MSH2 c.1165C>T (p.Arg389X) in UMD; and BRCA1 c.3700_3704delGTAAA (p.Val1234fsX8), CHEK2 c.1169A>C (p.Tyr390Ser), MSH2 c.2006-2A>T at our laboratory), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect of this variant (Bouvet_2019). Multiple submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=10) or likely benign/Benign (n=5). Based on the evidence outlined above, the variant was classified as benign.
GeneKor MSA	RCV000115458	SCV000822020	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003148646	SCV000838014	likely benign	Hereditary nonpolyposis colon cancer	2022-03-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587838	SCV000885705	uncertain significance	not provided	2017-09-22	criteria provided, single submitter	clinical testing	The MLH1 c.1360G>C;p.Gly454Arg is reported in the medical literature in individuals with Lynch syndrome (Auclair 2006, Lucci-Cordisco 2006, Loizidou 2014, and Hardt 2011). multiple computational analyses indicate the variant has a neutral effect on the MLH1 protein (Chao 2008). This variant is listed in the dbSNP variant database (rs63750527) and in the Genome Aggregation Database in 28 individuals (28 out of 277032 alleles). The p.Gly454Arg variant is classified by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) as a variant of uncertain significance because there is insufficient evidence about this variant (Variation ID: 89705). The glycine at this position is weakly conserved across species and computational algorithms (AlignGVGD, Polyphen2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. References: Chao et al. Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum Mutat. 2008; 29(6):852-860. Hardt et al. Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies. Fam Cancer. 2011;10(2):273-284. Loizidou et al. The mutational spectrum of Lynch syndrome in cyprus. PLoS One. 2014; 9(8):e105501. Lucci-Cordisco et al. The use of microsatellite instability, immunohistochemistry and other variables in determining the clinical significance of MLH1 and MSH2 unclassified variants in Lynch syndrome. Cancer Biomark. 2006;2(1-2):11-27.
Fulgent Genetics, Fulgent Genetics	RCV000764492	SCV000895563	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	RCV000115458	SCV000902779	likely benign	Hereditary cancer-predisposing syndrome	2016-01-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410484	SCV001308773	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-28	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587838	SCV002009375	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115458	SCV002528643	likely benign	Hereditary cancer-predisposing syndrome	2021-02-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200984	SCV002760288	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149732	SCV003838107	likely benign	Breast and/or ovarian cancer	2021-08-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410484	SCV004018180	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	criteria provided, single submitter	clinical testing	This variant is considered 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]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.