Submissions for variant NM_000179.3(MSH6):c.3119_3120del (p.Asn1039_Phe1040insTer)

dbSNP: rs267608042

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074804	SCV000108015	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000486939	SCV000568724	pathogenic	not provided	2021-01-08	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; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Roncari 2007, Cruz-Correa 2015, Rossi 2017, Sunga 2017); This variant is associated with the following publications: (PMID: 28449805, 17718861, 25782445, 31297337, 28874130)
Ambry Genetics	RCV000491377	SCV000580131	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	clinical testing	The c.3119_3120delTT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3119 to 3120, causing a translational frameshift with a predicted alternate stop codon (p.F1040*). This mutation has been reported in an individual diagnosed with duodenal cancer at age 57 and whose tumor showed microsatellite instability and absent MSH6 on IHC (Roncari B et al. Clin Genet. 2007 Sep;72(3):230-7). This mutation has also been subsequently identified in several Hispanic individuals with Lynch syndrome (Cruz-Correa M et al. Fam. Cancer 2015 Sep;14:415-25; Sunga AY et al. Cancer Genet 2017 Apr;212-213:1-7; Rossi BM et al. BMC Cancer 2017 Sep;17:623). Of note, this alteration is also designated as p.Phe1040Ter, c.3119delTT, and p.Phe1040Terfs 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.
Invitae	RCV000531248	SCV000624817	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-06-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89339). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (rs267608042, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Phe1040*) 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).
Color Diagnostics, LLC DBA Color Health	RCV000491377	SCV000685354	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides 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 identified in 1/248958 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	RCV001175453	SCV001339019	pathogenic	Hereditary nonpolyposis colon cancer	2020-03-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3119_3120delTT (p.Phe1040X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 248958 control chromosomes. c.3119_3120delTT has been reported in the literature in individuals affected with Hereditary Non-Polyposis Colon Cancer and lung cancer (Sun_2019, Cruz-Correa_2015, Roncari_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486939	SCV001470564	pathogenic	not provided	2020-03-16	criteria provided, single submitter	clinical testing	The MSH6 c.3119_3120del (p.Phe1040*) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant has been reported in the published literature in individuals and families affected with Lynch syndrome associated cancers (PMIDs: 17718861 (2007), 25782445 (2015), 31297337 (2019)). The frequency of this variant in the general population, 0.000004 (1/248958 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000486939	SCV001501270	pathogenic	not provided	2020-09-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000486939	SCV002010098	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003224862	SCV003921088	pathogenic	Lynch syndrome 5	2023-03-03	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP
Myriad Genetics, Inc.	RCV003224862	SCV004185715	pathogenic	Lynch syndrome 5	2023-08-22	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	RCV003466946	SCV004196357	pathogenic	Endometrial carcinoma	2021-09-03	criteria provided, single submitter	clinical testing