Submissions for variant NM_000249.4(MLH1):c.702G>A (p.Glu234=)

gnomAD frequency: 0.00041  dbSNP: rs35908749

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030231	SCV000106840	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Synonymous substitution with no splicing aberration, treated with NMD inhibitor
GeneDx	RCV000212521	SCV000170291	benign	not specified	2014-01-23	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	RCV000126773	SCV000212846	likely benign	Hereditary cancer-predisposing syndrome	2014-08-01	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.
Invitae	RCV001082760	SCV000253142	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000126773	SCV000537423	likely benign	Hereditary cancer-predisposing syndrome	2015-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588685	SCV000696177	likely benign	not provided	2016-05-03	criteria provided, single submitter	clinical testing	Variant summary: This synonymous variant is located 25 nts downstream of intron-exon junction in coding region. 3/5 splice-site tools predict the variant not to have effect on splicing and two independent functional studies showed that this variant does not have effect on normal splicing (Borras et al 2012 and Thompson et al 2013). This variant has been reported in multiple HNPCC patients mostly of European origin, albeit some of them did not fulfilling Amsterdam criteria for HNPCC diagnosis. In one patient, another variant that could explain the phenotype was also detected. The variant was found at a frequency of 0.0392% in the general population (47/119650 chromosomes), clustered mainly in the population of European origin with no homozygous occurrence. This frequency in general population is lower than the maximal expected allele frequency (0.07%) for pathogenic MLH1 variant. Lastly, reputable databases and diagnostic centers classify the variant as likely benign/benign/neutral. Taken together, this variant has been classified as likely benign.
Mendelics	RCV000987156	SCV001136383	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588685	SCV001153837	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MLH1: BP4, BP7
Illumina Laboratory Services, Illumina	RCV000987156	SCV001305704	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). 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.
Sema4, Sema4	RCV000126773	SCV002528775	benign	Hereditary cancer-predisposing syndrome	2020-10-20	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212521	SCV002552438	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149583	SCV003838862	likely benign	Breast and/or ovarian cancer	2021-06-24	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000126773	SCV004228001	benign	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000030231	SCV004840895	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000212521	SCV000691850	likely benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000126773	SCV000886686	likely benign	Hereditary cancer-predisposing syndrome	2018-10-04	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356606	SCV001551822	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MLH1 p.Glu234Glu variant was identified in 5 of 1752 proband chromosomes (frequency: 0.003) from individuals or families with colon cancer or hereditary non-polyposis colorectal cancer and was not identified in 604 control chromosomes from healthy individuals (Borras 2012, Curia 1999, Grabowski 2004, Caldes 2002). The variant was also identified the following databases: dbSNP (ID: rs35908749) as “With Likely benign allele”, ClinVar (classified as benign 2x by GeneDx and Invitae; and classified as likely benign 4x by InSiGHT, Ambry Genetics, Color Genomics, Laboratory Corporation of America), Clinvitae (classified 2x as benign by GeneDx and Invitae; 4x as likely benign by Ambry Genetics, Color Genomics, InSiGHT, Laboratory Corporation of America), UMD-LSDB (observed 8x), Insight Colon Cancer Gene Variant Database (5x pathogenicity unknown, 1x probably no pathogenicity), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (6 references, all classified as “probably does not affect function”). The variant was not identified in COGR, COSMIC, MutDB, or the Zhejiang Colon Cancer Databases. The variant was identified in control databases in 110 of 276966 chromosomes at a frequency of 0.0004 in the following populations: Latino in 27 of 34398 chromosomes (freq. 0.0008); European non-Finnish in 67 of 126622 chromosomes (freq. 0.0005); South Asian in 10 of 30766 chromosomes (freq. 0.0003); population listed as Other in 2 of 6458 chromosomes (freq. 0.0003); and African in 3 of 23948 chromosomes (freq. 0.0001) increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). This variant was identified in a patient with endometrial cancer whose family meets Amsterdam criteria and was negative for MLH1 by IHC, however this variant did not affect mRNA processing or stability and the authors conclude that the variant is likely neutral (Borras 2012). Additionally, this patient was found to have two other MLH1 missense variants which resulted in exon 9 skipping and a truncated protein. This variant was also observed in a patient with colon cancer and resulted in a modest germline transcript unbalance in a primer extension assay (Curia 1999). The p.Glu234Glu variant is not expected to have clinical significance because it does not result in a change of amino acid. Three of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing however this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000588685	SCV001921642	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588685	SCV001954562	likely benign	not provided		no assertion criteria provided	clinical testing