Submissions for variant NM_000249.4(MLH1):c.298C>T (p.Arg100Ter)

gnomAD frequency: 0.00001  dbSNP: rs63751221

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030223	SCV000106619	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030223	SCV000052890	pathogenic	Lynch syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
GeneDx	RCV000220956	SCV000279069	pathogenic	not provided	2021-10-11	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; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Wang 1999, Peel 2000, Samowitz 2001, Hampel 2005, Mangold 2005, Mueller-Koch 2005, Gylling 2007, Lagerstedt- Robinson 2007, Tang 2009, Yurgelun 2015, Lagerstedt- Robinson 2016, Bruegl 2017, Cloyd 2019); Not observed 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: 15872200, 17312306, 17267619, 10995807, 29950348, 30382883, 30998989, 25525159, 10480359, 18415027, 25980754, 15955785, 15849733, 15235038, 15475387, 11606497, 19419416, 27601186, 27965287, 29866690, 29238914)
Invitae	RCV000524287	SCV000543562	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg100*) 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 hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 10480359, 11606497, 14512394, 15235038, 15872200, 17312306). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36550). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000220956	SCV000601394	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MLH1 protein synthesis. The frequency of this variant in the general population, 0.0000087 (1/114534 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals and families affected with Lynch syndrome (PMID: 25980754 (2015), 21642682 (2011), 17453009 (2007), 17312306 (2007), 17267619 (2007), 15955785 (2005), 15872200 (2005), 15849733 (2005), 15235038 (2004), 11606497 (2001), 10995807 (2000)). Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV000569466	SCV000662011	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-13	criteria provided, single submitter	clinical testing	The p.R100* pathogenic mutation (also known as c.298C>T), located in coding exon 3 of the MLH1 gene, results from a C to T substitution at nucleotide position 298. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation is well described in the literature and has been reported in multiple individuals and families with hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (Taylor CF et al. Hum. Mutat., 2003 Dec;22:428-33; Renkonen E et al. J Med Genet, 2004 Jul;41:e95; Hampel H et al. N Engl J Med, 2005 May;352:1851-60; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Lagerstedt Robinson K et al. J Natl Cancer Inst, 2007 Feb;99:291-9; Gylling A et al. Gut, 2007 Jul;56:926-33; Choi YH et al. Hered Cancer Clin Pract, 2009 Aug;7:14; Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Stojcev Z et al. Acta Biochim Pol, 2013 Jun;60:195-8; Kamiza AB et al. PLoS One, 2015 Jun;10:e0130018; Guindalini RS et al. Gastroenterology, 2015 Nov;149:1446-53; Azizi AH et al. BMJ Case Rep, 2018 Jun;2018). In one study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as "100 Arg>stop (CGA>TGA)," R100X, and p.Arg100X 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	RCV000576742	SCV000677732	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569466	SCV000689871	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000220956	SCV001450047	pathogenic	not provided	2019-04-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000220956	SCV003821551	pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576742	SCV004018171	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	RCV000576742	SCV004195048	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000030223	SCV004847549	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Arg100X variant in MLH1 has been reported in at least 10 individuals with Lynch syndrome and segregated with disease in at least 6 affected individuals from 2 families (Wang 1999, Samowitz 2001, Renknen 2003, Renkonen 2004, Taylor 2003 Mangold 2005, Choi 2009, Hampel 2005, Lagerstedt 2007, Peel 2000, Gylling 2007). It was absent from large population studies. This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 36550). This nonsense variant leads to a premature termination codon at position 100, which is predicted to lead to a truncated or absent protein. Loss of function of the MLH1 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PP1_Moderate.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000030223	SCV000592344	pathogenic	Lynch syndrome		no assertion criteria provided	clinical testing	The MLH1 p.Arg100X variant was identified in 10 of 8938 proband chromosomes from individuals with colon or gastric cancer and was absent in 146 control chromosomes (Choi 2009, Gylling 2007, Hampel 2005, Lagerstedt Robinson 2007, Mangold 2005, Peel 2000, Samowitz 2001, Taylor 2003). The variant was also identified in dbSNP (ID: rs63751221) “With pathogenic allele”, HGMD, UMD (44X), “Mismatch Repair Genes Variant Database”, and the COSMIC database. The p.Arg100X variant leads to a premature stop codon at position 100, 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. Three studies showed microsatellite instability in tumours from patients positive for the variant (Gylling 2007, Hampel 2005, Samowitz 2001); Gylling (2007) also showed loss of heterozygosity of MLH1 in the tumour analysed. In addition, Lagerstedt Robinson (2007) demonstrated a loss of MLH1 protein expression in a tumour from a patient with the variant. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000220956	SCV000691844	pathogenic	not provided		no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001250008	SCV001423909	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000220956	SCV001740279	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000220956	SCV001958536	pathogenic	not provided		no assertion criteria provided	clinical testing