Submissions for variant NM_000249.4(MLH1):c.1459C>T (p.Arg487Ter)

dbSNP: rs63749795

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075218	SCV000106210	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000128870	SCV000172727	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-10	criteria provided, single submitter	clinical testing	The p.R487* pathogenic mutation (also known as c.1459C>T), located in coding exon 13 of the MLH1 gene, results from a C to T substitution at nucleotide position 1459. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several with family histories meeting Amsterdam criteria and whose tumors demonstrated high microsatellite instability and/or loss of MLH1/PMS2 on immunohistochemistry (IHC) (Fidalgo P et al. Eur. J. Hum. Genet. 2000 Jan;8:49-53; Pigatto F et al. Hered Cancer Clin Pract, 2004 Nov;2:175-84; Casey G et al. JAMA. 2005 Feb;293:799-809; Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702; Yap HL et al. Fam. Cancer. 2009 Aug;8:85-94; Win AK et al. J. Med. Genet. 2011 Aug;48:530-4; De Lellis L et al. PLoS One, 2013 Nov;8:e81194; Carneiro da Silva F et al. PLoS One, 2015 Oct;10:e0139753; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Lee J et al. Gynecol Oncol, 2018 10;151:153-158; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739). 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.
Invitae	RCV000524240	SCV000253786	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg487*) 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 colorectal cancer and Lynch syndrome (PMID: 10713887, 14635101, 15849733, 15870828, 21636617, 21681552, 24344984). ClinVar contains an entry for this variant (Variation ID: 89744). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000255034	SCV000321897	pathogenic	not provided	2023-10-09	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 15222003, 24344984, 27601186, 24333619, 10713887, 17473388, 31830689, 15870828, 9777949, 15849733, 24278394, 15996210, 21636617, 17312306, 16181381, 17505997, 18726168, 15713769, 22776989, 28874130, 27064304, 11920650, 10995807, 26437257, 30521064, 30322717, 31350202, 31589614, 30787465, 31494577, 31844177, 31118792, 14635101, 30077346, 21681552, 20233461, 33532831, 36073830)
Color Diagnostics, LLC DBA Color Health	RCV000128870	SCV000684746	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 13 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals and families affected with colorectal cancer and/or Lynch syndrome (PMID: 10713887, 10995807, 11920650, 14635101, 15849733, 16181381, 18726168, 21636617, 21681552, 22776989, 27064304, 27300552, 27601186, 30521064, 31118792). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075218	SCV000696112	pathogenic	Lynch syndrome	2016-07-20	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1459C>T (p.Arg487X) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not found in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Counsyl	RCV000662808	SCV000785641	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2017-10-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763103	SCV000893645	pathogenic	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000075218	SCV000914321	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000255034	SCV001449741	pathogenic	not provided	2019-02-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255034	SCV001469793	pathogenic	not provided	2020-03-26	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Revvity Omics, Revvity	RCV000255034	SCV002017495	pathogenic	not provided	2022-04-25	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000662808	SCV002579597	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-11-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662808	SCV004018172	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 termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000662808	SCV004192965	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000075218	SCV004841016	pathogenic	Lynch syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 13 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals and families affected with colorectal cancer and/or Lynch syndrome (PMID: 10713887, 10995807, 11920650, 14635101, 15849733, 16181381, 18726168, 21636617, 21681552, 22776989, 27064304, 27300552, 27601186, 30521064, 31118792). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353584	SCV000592406	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MLH1 p.Arg487X variant was identified in 14 of 7202 proband chromosomes (frequency: 0.002) from individuals or families with Lynch Syndrome (Caldes 2002, Casey 2005, DeLeon 2007, Fidalgo 2000, Lage 2004, Lee 2005, Leung 1998, Losi 2005, Mangold 2005, Mangold 2005, Pedroni 2007, Peel 2000, Lagerstedt Robinson 2007). The variant was also previously identified by our laboratory in 2 individuals with Lynch Syndrome. The variant was identified in dbSNP (ID: rs63749795), “With Pathogenic allele”, COSMIC 1X, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database” as class 5 - pathogenic, “Zhejiang Colon Cancer Database” as “pathogenic”, ClinVar database (submitted by “InSiGHT”), and UMD (27 X as a causal variant). A tumour with the variant was also identified as MLH1 deficient and MSI-H (within the “InSiGHT Colon Cancer Database”), and tumours described in the literature also demonstrated microsatellite instability and/or deficiency of MLH1 by immunohistochemistry (Caldes 2002, Casey 2005, Lagerstedt Robinson 2007, Lee 2005, Losi 2005, Mangold 2005, Pedroni 2007). The p.Arg487X variant leads to a premature stop codon at position 487, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MLH1 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000255034	SCV000691862	pathogenic	not provided		no assertion criteria provided	clinical testing
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093677	SCV001250858	pathogenic	Lynch syndrome 1		no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249944	SCV001423886	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000255034	SCV001740684	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255034	SCV001951125	pathogenic	not provided		no assertion criteria provided	clinical testing