Submissions for variant NM_000249.4(MLH1):c.1489dup (p.Arg497fs)

dbSNP: rs63750855

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075227	SCV000106219	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000201993	SCV000211079	pathogenic	not provided	2018-07-09	criteria provided, single submitter	clinical testing	This duplication of one nucleotide is denoted MLH1 c.1489dupC at the cDNA level and p.Arg497ProfsX6 (R497PfsX6) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACCCCC[dupC]GGAG. The duplication causes a frameshift, which changes an Arginine to a Proline at codon 497, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Also published as MLH1 c.1489_1490insC using alternate nomenclature, this variant has been reported in many individuals and families with Lynch syndrome (Kurzawski 2002, Behrens 2003, Mangold 2005, Wolf 2006, Bonadona 2011, Buchanan 2014, Magnani 2015). MLH1 c.1489dupC has also been reported in at least one individual with a clinical diagnosis of Muir-Torre syndrome (Mangold 2007). Additionally, this variant has been observed in the germline of at least two individuals with breast cancer; one breast tumor demonstrated loss of MLH1 protein on immunohistochemistry and the other breast tumor demonstrated loss of heterozygosity (Lotsari 2012, Pedroni 2014). Lastly, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). Based on currently available evidence, we consider MLH1 c.1489dupC to be pathogenic.
Ambry Genetics	RCV000162490	SCV000212869	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-07	criteria provided, single submitter	clinical testing	The c.1489dupC pathogenic mutation, located in coding exon 13 of the MLH1 gene, results from a duplication of C at nucleotide position 1489, causing a translational frameshift with a predicted alternate stop codon (p.R497Pfs*6). This mutation has been reported in multiple studies of patients with Lynch syndrome, including those meeting Amsterdam criteria and/or with tumors demonstrating microsatellite instability or loss of MLH1 protein expression by IHC (Moslein G et al. Hum. Mol. Genet., 1996 Sep;5:1245-52; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Papp J et al. World J Gastroenterol, 2007 May;13:2727-32; Kast K et al. Arch Gynecol Obstet, 2016 11;294:1299-1303). This mutation was also present in individuals from HNPCC families with Muir-Torre features (Mangold E et al. Br J Dermatol, 2007 Jan;156:158-62), small bowel cancer (Schulmann K et al. Gastroenterology, 2005 Mar;128:590-9), breast cancer (Lotsari JE et al. Breast Cancer Res., 2012 Jun;14:R90), and a neuroendocrine pancreatic tumor (Brieger A et al. Fam Cancer, 2011 Sep;10:591-5). Of note, this mutation is also designated as c.1489_1490insC and 495insC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000412044	SCV000489202	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2016-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV000684774	SCV000543569	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg497Profs*6) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome or Lynch syndrome associated cancers (PMID: 1756143, 8872463, 12810663, 15849733, 15926618, 18566915, 21598002, 22691310, 23695190, 24323032, 26053027). ClinVar contains an entry for this variant (Variation ID: 89753). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000075227	SCV000592407	pathogenic	Lynch syndrome	2016-03-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000201993	SCV000601357	pathogenic	not provided	2016-02-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000412044	SCV001251424	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2019-10-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192571	SCV001360798	pathogenic	Hereditary nonpolyposis colon cancer	2019-03-26	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1489dupC (p.Arg497ProfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 277234 control chromosomes (gnomAD). c.1489dupC has been reported in the literature in multiple individuals affected with Lynch Syndrome (Kamiza_2015, Kurzawski_2006, Kondo_2003). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that there was no interaction between the predicted truncated protein and PMS2 (Kondo_2003). Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000201993	SCV001449656	pathogenic	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000201993	SCV002009373	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000201993	SCV003821606	pathogenic	not provided	2023-11-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000201993	SCV004011451	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	MLH1: PVS1, PM2
Myriad Genetics, Inc.	RCV000412044	SCV004018173	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
All of Us Research Program, National Institutes of Health	RCV000075227	SCV004841021	pathogenic	Lynch syndrome	2023-05-31	criteria provided, single submitter	clinical testing	The c.1489dup (p.Arg497Profs*6) variant of the MLH1 gene creates a frameshift resulting in a premature termination codon that is predicted to lead to absent or truncated protein product. This variant has been reported in multiple individuals (>20) affected with Lynch syndrome associated phenotypes including colorectal cancer, breast cancer, endometrial cancer, small bowel cancer, and hereditary nonpolyposis colorectal cancer (HNPCC) (PMID: 17199584, 15849733, 8872463, 27535758, 15765394, 23695190, 15926618). In addition, this variant has been found in breast ductal tumors demonstrating microsatellite instability and loss of MLH1 protein expression by immunohistochemistry (PMID: 22691310). In vitro yeast two-hybrid assay demonstrated that the predicted truncated protein failed to interact with PMS2 protein (PMID:?12810663). Loss of function variants of the MLH1 gene are known to be pathogenic (PMID: 14635101, 15942939, 16955466, 15713769, 24362816, 33468175). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 8571956, 12810663, 15849733, 20459533) and by several ClinVar submitters (ClinVar ID: 89754, 89888, 89889, 439171). This variant is absent in the general population database (gnomAD) and classified as pathogenic by expert panel (ClinVar ID: 89753). Therefore, the c.1489dup (p.Arg497Profs*6) variant in the MLH1 gene is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000201993	SCV000257052	pathogenic	not provided		no assertion criteria provided	research
CZECANCA consortium	RCV001270941	SCV001451745	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000201993	SCV001905870	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000201993	SCV001970545	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV001804812	SCV002054053	not provided	Lynch syndrome 1		no assertion provided	literature only
CZECANCA consortium	RCV003128138	SCV003804358	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing