Submissions for variant NM_000179.3(MSH6):c.651dup (p.Lys218Ter)

gnomAD frequency: 0.00001  dbSNP: rs63750955

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075018	SCV000108239	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000235180	SCV000149347	pathogenic	not provided	2020-07-07	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; Also known as MSH6 217insT, MSH6 650insT, and MSH6 651_652insT; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Wu 1999, Plaschke 2000, Wu 2001, Berends 2002, Berends 2003, Hendriks 2004, Domingo 2005, Kets 2006, Overbeek 2007, Ramsoekh 2008, Steinke 2008, Ou 2009, van der Post 2010); This variant is associated with the following publications: (PMID: 16636019, 15782118, 15483016, 10521294, 20591884, 11586295, 18301448, 14645426, 18521850, 17117178, 18625694, 15236168, 10699937, 11709755, 20028993, 17453009, 12373605, 21081928, 19156873, 31589614)
Ambry Genetics	RCV000202569	SCV000213905	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-16	criteria provided, single submitter	clinical testing	The c.651dupT pathogenic mutation (also known as p.K218*), located in coding exon 4 of the MSH6 gene, results from a duplication of T at nucleotide position 651. This changes the amino acid from a lysine to a stop codon within coding exon 4. In one study, this mutation was identified in three individuals with suspected HNPCC (Wu Y et al. Am J Hum Genet. 1999 Nov;65(5):1291-8). This mutation was also reported in an individual diagnosed with colon cancer at the age of 61, prostate cancer at the age of 67, and both ureter and bladder cancers at the age of 73. Immunohistochemistry (IHC) studies of the bladder tumor were reported to have absent MSH2 staining (van der Post RS et al. J Med Genet. 2010 Jul;47(7):464-70). Furthermore, this mutation has been identified in multiple other individuals with a clinical suspicion of Lynch syndrome and/or tumors exhibiting MSI-H and loss of MSH6 on IHC (Kets CM et al. Br. J. Cancer. 2006 Dec;95:1678-82; Steinke V et al. Eur. J. Hum. Genet. 2008 May;16(5):587-92; Ramsoekh D et al. Gut 2008 Nov;57(11):1539-44). 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	RCV000524211	SCV000283853	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys218*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in population databases (rs63750955, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and Lynch syndrome (PMID: 2059188, 10521294, 17453009, 18625694, 20028993). This variant is also known as 217insT. ClinVar contains an entry for this variant (Variation ID: 8932). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000202569	SCV000685513	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-27	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple families affected with Lynch syndrome and is considered to be a founder mutation in the Dutch population (PMID: 11709755, 25345868). This variant has been identified in 1/31412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 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	RCV002223129	SCV000695923	pathogenic	Hereditary nonpolyposis colon cancer	2022-03-18	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.651dupT (p.Lys218X) 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 allele was found at a frequency of 1.3e-05 in 150984 control chromosomes (gnomAD v3.1 database, genomes dataset). c.651dupT has been reported in the literature in multiple individuals affected with colorectal cancer and other tumors that belong to the Lynch Syndrome tumor spectrum (e.g. Plaschke_2000, Hendricks_2004, Kets_2006, Carnevali_2021); in some of these cases the lack of MSH6 protein on immunohistochemistry and/or high microsatellite instability was also noted in the associated tumor samples. 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. Seven other ClinVar submitters, have assessed the variant since 2014, and all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000009487	SCV000744289	pathogenic	Lynch syndrome 5	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235180	SCV000888295	pathogenic	not provided	2019-09-12	criteria provided, single submitter	clinical testing	This variant causes the premature termination of MSH6 protein synthesis. In addition, this variant has been reported in families suspected of HNPCC and in an individual with urothelial carcinoma in the published literature (PMID: 10521294 (1999), PMID: 20591884 (2010)). Based on the available information, this variant is classified as pathogenic.
MGZ Medical Genetics Center	RCV002288477	SCV002581724	pathogenic	Endometrial carcinoma	2022-08-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496313	SCV002811873	pathogenic	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-05-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000235180	SCV003820189	pathogenic	not provided	2022-05-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000009487	SCV004188317	pathogenic	Lynch syndrome 5	2023-08-10	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	RCV002288477	SCV004195837	pathogenic	Endometrial carcinoma	2023-02-12	criteria provided, single submitter	clinical testing
OMIM	RCV000009487	SCV000029705	pathogenic	Lynch syndrome 5	2001-10-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000235180	SCV000592572	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000009487	SCV000734212	pathogenic	Lynch syndrome 5		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000235180	SCV001906232	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV001804722	SCV002054079	not provided	Lynch syndrome 1		no assertion provided	literature only