Submissions for variant NM_000249.4(MLH1):c.637G>A (p.Val213Met)

gnomAD frequency: 0.00818  dbSNP: rs2308317

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075789	SCV000106799	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
GeneDx	RCV000121357	SCV000170290	benign	not specified	2014-01-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000128927	SCV000172797	benign	Hereditary cancer-predisposing syndrome	2014-10-22	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Eurofins Ntd Llc (ga)	RCV000121357	SCV000232494	benign	not specified	2014-12-29	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000075789	SCV000257653	benign	Lynch syndrome	2015-06-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083249	SCV000262382	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094789	SCV000443329	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2018-02-22	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121357	SCV000539631	benign	not specified	2016-03-28	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: ExAC: 3.0% African chromosomes
Genetic Services Laboratory, University of Chicago	RCV000121357	SCV000595800	likely benign	not specified	2016-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034547	SCV000604230	benign	not provided	2018-02-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128927	SCV000684855	benign	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121357	SCV000805978	benign	not specified	2017-01-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128927	SCV002528764	benign	Hereditary cancer-predisposing syndrome	2020-10-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121357	SCV002760280	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000128927	SCV002819213	benign	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149605	SCV003838860	benign	Breast and/or ovarian cancer	2021-06-28	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001094789	SCV004015883	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034547	SCV004185047	benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	MLH1: BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000034547	SCV005245160	benign	not provided		criteria provided, single submitter	not provided
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034547	SCV000043320	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000121357	SCV000085537	not provided	not specified	2013-09-19	no assertion provided	reference population
Mayo Clinic Laboratories, Mayo Clinic	RCV000121357	SCV000257109	benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128927	SCV000788025	benign	Hereditary cancer-predisposing syndrome	2017-11-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355297	SCV001550141	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MLH1 p.Val213Met variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs2308317) as With Benign ,Uncertain significance allele , ClinVar (classified as benign by InSight, GenDx, Ambry Genetics, Invitae; classified as likely benign by Illumina), Clinvitae (classified as benign by ClinVar), UMD-LSDB (3X as neutral), Insight Colon Cancer Gene Variant Database (8X class 1), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 733(11 homozygous) of 276886 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 671 of 24030 chromosomes (freq: 0.028). Functional analysis of human MLH1 variants using yeast identify the variant has normal EXO1-binding, normal PMS2-binding and normal MMR function (Kondo 2003, Takahashi 2007). The variant functioned like the WT MLH1 in all of the assays in Raevaara (2005) with normal MMR function, normal nuclear concentration of MLH1 and normal nuclear concentration of the MLH1-PMS2 heterodimer. In addition, the variant has no effect on splicing in the pCAS ExVivo SplicingAssay (Tournier 2008) and concordant with patient RNA. The p.Val213 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Histidine kinase-like ATPase, ATP-binding domain DNA mismatch repair protein family Ribosomal protein S5 domain 2-type fold functional domains increasing the likelihood that it may have clinical significance. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000121357	SCV001807560	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000121357	SCV001920437	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121357	SCV001952491	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000121357	SCV001966844	benign	not specified		no assertion criteria provided	clinical testing