Submissions for variant NM_000249.4(MLH1):c.676C>T (p.Arg226Ter)

dbSNP: rs63751615

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075801	SCV000106813	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000202205	SCV000149394	pathogenic	not provided	2019-08-22	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 a significant frequency in large population cohorts (Lek 2016); 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: 27601186, 25980754, 28514183, 10874307, 21056691, 21868491, 21247423, 20924129, 20045164, 19690142, 18307539, 15655560, 9927033, 8872463, 23047549, 25525159, 17889038, 22949379, 15849733, 12624141, 21879275, 22776989, 9472100, 24344984, 24456667, 28445943, 26681312, 28449805, 28944238, 11343035, 28502729, 29478780, 28874130, 30521064, 30720243, 30262796, 29505604, 30998989, 29625052, 30217226, 32719484)
Ambry Genetics	RCV000115485	SCV000212825	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	clinical testing	The p.R226* pathogenic mutation (also known as c.676C>T), located in coding exon 8 of the MLH1 gene, results from a C to T substitution at nucleotide position 676. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has been detected in multiple families meeting Amsterdam Criteria for a clinical diagnosis of Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch syndrome), several with tumors demonstrating microsatellite instability and loss of MLH1 protein on immunohistochemistry (Moslein G et al. Hum Mol Genet, 1996 Sep;5:1245-52; Marcos I et al. J Pediatr, 2006 Jun;148:837-9; Mueller J et al. Cancer Res, 2009 Sep;69:7053-61; Coolbaugh-Murphy MI et al. Hum Mutat, 2010 Mar;31:317-24; Chang SC et al. Surgery, 2010 May;147:720-8; Jasperson KW et al. Fam Cancer, 2010 Jun;9:99-107; Giráldez MD et al. Clin Cancer Res, 2010 Nov;16:5402-13; Limburg PJ et al. Clin Gastroenterol Hepatol, 2011 Jun;9:497-502; Castillejo A et al. BMC Med. Genet., 2011;12:12; Pal T et al. Br J Cancer, 2012 Nov;107:1783-90; Pérez-Carbonell L et al. Gut, 2012 Jun;61:865-72; Hinrichsen I et al. Mol Cancer, 2014 Jan;13:11; Dominguez-Valentin M et al. Front Oncol, 2016 Aug;6:189; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Zhang J et al. Oncotarget, 2017 Apr;8:24533-24547; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Sunga AY et al. Cancer Genet, 2017 04;212-213:1-7; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Dámaso E et al. Cancers (Basel), 2020 Jul;12:). This mutation has been reported as homozygous in individuals with features of constitutional mismatch repair deficiency (CMMRD) syndrome (Ricciardone MD et al. Cancer Res, 1999 Jan;59:290-3; Apessos A et al. Br J Cancer, 2005 Jan;92:396-404). This mutation has also been reported in 1/327 Mexican patients with a personal and/or family history suspicious for hereditary breast and ovarian cancer syndrome (Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:). 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	RCV000524311	SCV000284071	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg226*) 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 present in population databases (rs63751615, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and Lynch syndrome (PMID: 8872463, 10874307, 15655560, 15849733, 17889038, 21247423, 23047549, 24344984). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17087). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202205	SCV000601407	pathogenic	not provided	2021-05-12	criteria provided, single submitter	clinical testing	This variant causes the premature termination of MLH1 protein synthesis. In the published literature, this variant has been reported in individuals and families with Lynch syndrome (PMIDs: 32635641 (2020), 28944238 (2017), 28874130 (2017), 21247423 (2011), 23047549 (2012)), and constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 17889038 (2008)). The frequency of this variant in the general population, 0.000004 (1/250982 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MLH1 mRNA splicing . Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000115485	SCV000689906	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This variant causes a C to T nucleotide change in exon 8 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 performed for this variant. This variant has been reported in multiple individuals and families affected with Lynch syndrome-associated cancer, many of whom met the Amsterdam II criteria (PMID: 9927033, 15655560, 15849733, 18307539, 19690142, 20045164, 20924129, 21247423, 24344984, 24362816, 27601186, 28514183, 28874130). This variant has also been reported in homozygous carriers affected with constitutional mismatch repair deficiency syndrome (PMID: 17889038), and has been shown to segregate with disease in families (PMID: 15655560, 21247423, 24362816). This variant has also been identified in an individual affected with ovarian cancer (PMID: 23047549). This variant has been identified in 1/250982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Counsyl	RCV000018616	SCV000785381	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2017-07-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075801	SCV000917661	pathogenic	Lynch syndrome	2018-08-14	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.676C>T (p.Arg226X) 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. Though the variant is located close to a canonical splice site, 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 245718 control chromosomes (gnomAD). The variant, c.676C>T, has been reported in the literature as a pathogenic variant in multiple individuals affected with Lynch Syndrome (e.g. Moslein 1996, Lagerstedt-Robinson 2016, Rossi 2017, Sunga 2017. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV000018616	SCV002580789	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-02-02	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000018616	SCV002761605	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-11-22	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137535	SCV003807079	pathogenic	Muir-Torré syndrome	2022-06-21	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated
Revvity Omics, Revvity	RCV000202205	SCV003821573	pathogenic	not provided	2022-04-11	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149572	SCV003838861	pathogenic	Breast and/or ovarian cancer	2021-09-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000018616	SCV004018205	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-16	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	RCV000018616	SCV004193071	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-07-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000075801	SCV004840892	pathogenic	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This variant causes a C to T nucleotide change in exon 8 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 performed for this variant. This variant has been reported in multiple individuals and families affected with Lynch syndrome-associated cancer, many of whom met the Amsterdam II criteria (PMID: 9927033, 15655560, 15849733, 18307539, 19690142, 20045164, 20924129, 21247423, 24344984, 24362816, 27601186, 28514183, 28874130). This variant has also been reported in homozygous carriers affected with constitutional mismatch repair deficiency syndrome (PMID: 17889038), and has been shown to segregate with disease in families (PMID: 15655560, 21247423, 24362816). This variant has also been identified in an individual affected with ovarian cancer (PMID: 23047549). This variant has been identified in 1/250982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
OMIM	RCV000018616	SCV000038899	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2001-05-01	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000202205	SCV000257111	pathogenic	not provided		no assertion criteria provided	research
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093685	SCV001250867	pathogenic	Lynch syndrome 1		no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249951	SCV001423893	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
OMIM	RCV001267883	SCV001446362	pathogenic	Mismatch repair cancer syndrome 1	2001-05-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202205	SCV001552418	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000202205	SCV001740166	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202205	SCV001953289	pathogenic	not provided		no assertion criteria provided	clinical testing