Submissions for variant NM_000249.4(MLH1):c.1975C>T (p.Arg659Ter)

dbSNP: rs63751310

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075444	SCV000106442	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000128869	SCV000172726	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-30	criteria provided, single submitter	clinical testing	The p.R659* pathogenic mutation (also known as c.1975C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at nucleotide position 1975. This changes the amino acid from an arginine to a stop codon within coding exon 17. This is a well-established mutation associated with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome and was first reported in a Finnish kindred fulfilling Amsterdam criteria (Nystrom-Lahti M et al. Hum. Mol. Genet. 1996 Jun;5(6):763-9). It has since been reported in multiple patients with personal and family histories suggestive of HNPCC/Lynch syndrome (Farrington SM et al. Am. J. Hum. Genet. 1998 Sep;63:749-59; Valentin MD et al. Fam. Cancer 2011 Dec;10:641-7; Schneider NB et al. Cancer Med. 2018 May;7(5):2078-2088). Functional analyses have demonstrated that this mutation causes aberrant mRNA splicing and skipping of exon 17 (Nystrom-Lahti M et al. Genes Chromosomes Cancer. 1999 Dec;26(4):372-5; Renkonen EJ et al. J. Med. Genet. 2004 Jul;41(7):e95;Ambry internal data). 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.
GeneDx	RCV000202252	SCV000321898	pathogenic	not provided	2019-08-23	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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18550572, 19224586, 18566915, 18561205, 24344984, 12810663, 25980754, 9718327, 9087566, 25525159, 8776590, 21681552, 28874130, 28724667, 10534773, 19698169, 26437257, 20167975, 10200055, 15713769, 15235038, 29575718, 28932927)
Invitae	RCV000524261	SCV000543616	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg659*) 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 (PMID: 8776590, 10534773, 15713769, 18561205, 19698169, 20167975, 24344984, 26437257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89962). 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	RCV000202252	SCV000889395	pathogenic	not provided	2022-01-14	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MLH1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with suspected and confirmed Lynch syndrome, and colorectal cancer (PMIDs: 20167975 (2020), 29575718 (2018), 28932927 (2018), 28874130 (2017), 26202870 (2015), 21681552 (2011), 8776590 (1996)). This variant was also demonstrated to segregate with disease in one family affected with Lynch syndrome (PMID: 20167975 (2020)). In functional studies, this variant has been shown to lead to aberrant mRNA splicing and exon skipping (PMIDs: 15235038 (2004), 12810663 (2003), 10534773 (1999)). Based on the available information, this variant is classified as pathogenic.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000075444	SCV000914324	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226186	SCV003922580	pathogenic	Hereditary nonpolyposis colon cancer	2023-03-21	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1975C>T (p.Arg659X) 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 251070 control chromosomes. c.1975C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (example, PMID: 21642682, 15342696, 25110875). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003451087	SCV004186301	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-24	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	RCV003451087	SCV004193077	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-03-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202252	SCV004243153	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202252	SCV000257077	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202252	SCV000592431	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000202252	SCV002034925	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202252	SCV002037370	pathogenic	not provided		no assertion criteria provided	clinical testing