Submissions for variant NM_000251.3(MSH2):c.1226_1227del (p.Gln409fs)

dbSNP: rs63750086

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076073	SCV000107088	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing a premature termination codon
GeneDx	RCV000212600	SCV000211228	pathogenic	not provided	2023-08-02	criteria provided, single submitter	clinical testing	Frameshift 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 significant frequency in large population cohorts (gnomAD); 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: 21778331, 16216036, 8872463, 17569143, 24244552, 19419416, 25712738, 26552419, 29360161, 28874130, 26681312, 30787465, 31692600, 31664942, 31830689, 31948886, 31615790)
Ambry Genetics	RCV000160629	SCV000212765	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-23	criteria provided, single submitter	clinical testing	The c.1226_1227delAG pathogenic mutation, located in coding exon 7 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 1226 to 1227, causing a translational frameshift with a predicted alternate stop codon (p.Q409Rfs*7). This alteration has been identified in numerous ethnically diverse individuals/ families with HNPCC/Lynch syndrome (Liu T et al. Genes Chromosomes Cancer. 2000 Jan;27:17-25; Mueller-Koch Y et al. Gut. 2005 Dec;54:1733-40; Lagerstedt Robinson K et al. J. Natl. Cancer Inst. 2007 Feb;99:291-9; Papp J et al. World J Gastroenterol. 2007 May;13:2727-32; Tang R et al. Clin Genet. 2009 Apr;75:334-45; Pérez-Cabornero L et al. Cancer Prev. Res. (Phila). 2011 Oct;4:1546-55; Egoavil C et al. PLoS ONE. 2013 Nov;8:e79737; Siraj AK et al. Cancer. 2015 Jun;121:1762-71; Goodfellow PJ et al. J. Clin. Oncol. 2015 Dec;33:4301-8). Additionally, this alteration has been identified in individuals with pancreatic, prostate, and urinary tract malignancies, as well as sebaceous carcinoma (Dudley B et al. Cancer 2018 Apr;124:1691-1700; Burris CKH et al. Case Rep Ophthalmol. May 2019;10:180-185; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev. 2020 01;29:193-199; Wu Y et al. Eur Urol Oncol. 2020 04;3:224-230). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000076073	SCV000266082	pathogenic	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000411649	SCV000489574	pathogenic	Lynch syndrome 1	2016-10-27	criteria provided, single submitter	clinical testing
Invitae	RCV000524336	SCV000548145	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln409Argfs*7) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 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 and endometrial cancer (PMID: 8872463, 15849733, 17569143, 19419416, 21778331, 24244552, 26552419, 26845104). ClinVar contains an entry for this variant (Variation ID: 90577). For these reasons, this variant has been classified as Pathogenic.
GenePathDx, GenePath diagnostics	RCV000411649	SCV000616340	pathogenic	Lynch syndrome 1	2017-08-17	criteria provided, single submitter	clinical testing	Diagnosed case of FAP
Color Diagnostics, LLC DBA Color Health	RCV000160629	SCV000684917	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 7 of the MSH2 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 individuals affected with Lynch syndrome (PMID: 8872463, 17569143, 25712738, 26552419). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Mendelics	RCV000076073	SCV000837829	pathogenic	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212600	SCV000888200	pathogenic	not provided	2018-06-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076073	SCV000917719	pathogenic	Lynch syndrome	2018-08-27	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1226_1227delAG (p.Gln409ArgfsX7) 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 246188 control chromosomes (gnomAD). The variant, c.1226_1227delAG, has been reported in the literature in multiple individuals affected with Lynch Syndrome (Goodfellow_2015, Mangold_2005). 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 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000212600	SCV001449631	pathogenic	not provided	2016-05-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411649	SCV004018414	pathogenic	Lynch syndrome 1	2023-03-23	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000411649	SCV004196915	pathogenic	Lynch syndrome 1	2022-02-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000411649	SCV004807341	pathogenic	Lynch syndrome 1	2024-03-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000076073	SCV004832635	pathogenic	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 7 of the MSH2 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 individuals affected with Lynch syndrome (PMID: 8872463, 17569143, 25712738, 26552419). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212600	SCV000592494	pathogenic	not provided		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000212600	SCV000691903	pathogenic	not provided		no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554324	SCV001775492	pathogenic	Ovarian cyst	2021-08-09	no assertion criteria provided	clinical testing