Submissions for variant NM_000249.4(MLH1):c.2152C>T (p.His718Tyr)

gnomAD frequency: 0.02345  dbSNP: rs2020873

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030220	SCV000106553	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035352	SCV000059000	benign	not specified	2011-12-14	criteria provided, single submitter	clinical testing	The His718Tyr variant (rs2020873) in MLH1 is present in various populations at f requencies ranging from ~1% to ~16% and is more common individuals with African ancestry. In addition, this variant was reported in patient and control chromoso mes with equal frequncy (Barnetson 2008, Moussa 2011, Weber 1999). Finally, func tional studies have shown the His718Tyr has no discernbile impact on the functio n of the MMR complex (Martinez 2010, Kondo 2003). Therefore this variant is beni gn and not expected to have clinical significance.
Eurofins Ntd Llc (ga)	RCV000035352	SCV000110266	benign	not specified	2013-09-10	criteria provided, single submitter	clinical testing
Invitae	RCV001081091	SCV000153886	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000035352	SCV000170301	benign	not specified	2013-10-18	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	RCV000157759	SCV000212715	benign	Hereditary cancer-predisposing syndrome	2014-11-18	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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000030220	SCV000257652	likely benign	Lynch syndrome	2015-02-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000035352	SCV000303149	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625495	SCV000443341	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2018-01-23	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000035352	SCV000604233	benign	not specified	2018-08-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000157759	SCV000684802	benign	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625495	SCV000745683	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-11	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000625495	SCV000781765	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000157759	SCV002528721	benign	Hereditary cancer-predisposing syndrome	2020-01-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000035352	SCV002550521	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000157759	SCV002819149	benign	Hereditary cancer-predisposing syndrome	2022-12-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149581	SCV003838873	benign	Breast and/or ovarian cancer	2021-10-29	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000625495	SCV004015877	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000030220	SCV004843287	benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034546	SCV000043331	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030220	SCV000052887	benign	Lynch syndrome	2011-10-26	no assertion criteria provided	clinical testing
ITMI	RCV000035352	SCV000085547	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144604	SCV000189931	benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000035352	SCV000257088	likely benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353518	SCV000592442	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MLH1 p.His718Tyr variant was identified in 6 of 2626 proband chromosomes (frequency: 0.002) from individuals with sporadic colorectal cancer or suspected HNPCC, none of whom met complete requirements of the Amsterdam or Bethesda criteria (Kim 2004, Kondo 2003, Takahashi 2007, Moussa 2011, Schafmayer 2007). This variant was also identified in 17 of 2254 control chromosomes from the above studies (frequency: 0.008), in the 1000 Genomes Project with a frequency of 0.028, and in the Exome Variant Server ESP Project with a frequency of 0.07 amongst African American alleles, suggesting that this variant may represent a benign polymorphism in certain populations. The variant was also reported in dbSNP (rs2020873) and LOVD. In vitro MMR assays and yeast hybrid-two assays examining the ability of the variant to repair a heteroduplex DNA with mismatch bases found that its activity was similar to that of wildtype (Kondo 2003, Takahashi 2007), suggesting that this is a nonpathogenic alteration. The p.His718 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.His718Tyr variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, we cannot determine the clinical significance of this variant with certainty at this time, although we would lean towards a more benign role for this variant. In summary, this variant is classified as predicted benign.
True Health Diagnostics	RCV000157759	SCV000788023	benign	Hereditary cancer-predisposing syndrome	2017-10-26	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035352	SCV001922338	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000035352	SCV001958947	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000035352	SCV002036958	benign	not specified		no assertion criteria provided	clinical testing