Submissions for variant NM_000249.4(MLH1):c.1959G>T (p.Leu653=)

gnomAD frequency: 0.00913  dbSNP: rs1800146

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030219	SCV000106434	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Synonymous substitution with no splicing aberration, >3 MSS CRC tumours, segregation LR <0.01 & MAF 0.01-1%
Invitae	RCV000524259	SCV000153861	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000153507	SCV000170299	benign	not specified	2013-10-25	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.
Eurofins Ntd Llc (ga)	RCV000153507	SCV000203027	benign	not specified	2014-03-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000126778	SCV000212672	benign	Hereditary cancer-predisposing syndrome	2016-10-25	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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	RCV000030219	SCV000257650	benign	Lynch syndrome	2015-07-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000126778	SCV000292111	benign	Hereditary cancer-predisposing syndrome	2014-11-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000153507	SCV000303147	benign	not specified		criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000610651	SCV000744682	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2015-09-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000610651	SCV000745681	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2015-05-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811212	SCV001156602	benign	not provided	2023-11-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000610651	SCV001305813	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.
Sema4, Sema4	RCV000126778	SCV002528698	benign	Hereditary cancer-predisposing syndrome	2020-03-21	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001811212	SCV002544786	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	MLH1: BP4, BP7, BS1, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000153507	SCV002550460	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030219	SCV000052886	benign	Lynch syndrome	2013-04-18	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000144610	SCV000189937	benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000153507	SCV000257075	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353935	SCV000592429	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Leu653Leu variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs1801426) with an average heterozygosity of 0.022+/-0.102, increasing the likelihood that this is a low frequency benign variant. The variant has been previously reported in the literature in 9 publications in 20 of 2288 proband chromosomes (frequency of 0.013) with colon cancer, breast cancer, prostate cancer and endometrial cancer, and was also identified in 39 of 2846 control chromosomes (frequency of 0.014), increasing the likelihood that this is a benign variant (Auclaire_16395668_2006, Buerstedde_ 8592341_1995, Christensen_18547406_2008, Fredriksson_16963262_2006, Kamory_14688830_2003, Lamberti_17095871_2006, Liu_9611074_1998, Scott_11112663_2001). In one report this variant was identified at a higher frequency in controls than in cases (Christensen_18547406_2008). In summary, based on the information above, this variant is classified as Benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000610651	SCV000734272	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000126778	SCV000788020	likely benign	Hereditary cancer-predisposing syndrome	2017-12-08	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000153507	SCV001798253	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000153507	SCV001905719	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000153507	SCV001920947	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000153507	SCV001953573	benign	not specified		no assertion criteria provided	clinical testing