Submissions for variant NM_000251.3(MSH2):c.1705_1706del (p.Glu569fs)

dbSNP: rs63750393

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030243	SCV000107273	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030243	SCV000052910	pathogenic	Lynch syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
GeneDx	RCV000115505	SCV000149414	pathogenic	not provided	2017-08-09	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH2 c.1705_1706delGA at the cDNA level and p.Glu569IlefsX2 (E569IfsX2) at the protein level. The normal sequence, with the bases that are deleted in braces, is AACA[GA]ATAT. The deletion causes a frameshift, which changes a Glutamic Acid to an Isoleucine at codon 569, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.1705_1706delGA, also reported as c.1705delAG and c.1704_1705delAG, has been reported in several families with Lynch syndrome (Apessos 2005, Mangold 2005, Kurzawski 2006, Stulp 2008, Choi 2009, Walsh 2010, Bauer 2011, De Lellis 2013). We consider this variant to be pathogenic.
Counsyl	RCV000409229	SCV000489543	pathogenic	Lynch syndrome 1	2016-10-21	criteria provided, single submitter	clinical testing
Invitae	RCV000627733	SCV000548247	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu569Ilefs*2) 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 breast cancer and prostate cancer and a family history of colorectal, duodenal and prostate cancer and Lynch syndrome (PMID: 11920650, 15655560, 15713769, 15849733, 16311127, 19698169, 20215533, 20587412, 20872076, 24278394). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1704_1705delAG. ClinVar contains an entry for this variant (Variation ID: 36569). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491995	SCV000580390	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	The c.1705_1706delGA pathogenic mutation, located in coding exon 11 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 1705 to 1706, causing a translational frameshift with a predicted alternate stop codon (p.E569Ifs*2). This mutation has been detected in multiple individuals and families affected with HNPCC/Lynch syndrome (Wijnen J et al. Am. J. Hum. Genet. 1997 Aug;61:329-35; Nomura S et al. Biochem. Biophys. Res. Commun. 2000 Apr;271:120-9; Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Westenend PJ et al. Hum. Pathol. 2005 Dec;36:1322-6; Kurzawski G et al. Clin. Genet. 2006 Jan;69:40-7; Julié C et al. Am. J. Gastroenterol. 2008 Nov;103:2825-35; quiz 2836; Sunga AY et al. Cancer Genet. 2017 Apr;212-213:1-7; Rossi BM et al. BMC Cancer 2017 Sep;17:623). A different alteration (c.1704_1705delAG) resulting in the same alternate stop codon was identified in probands with prostate and breast tumors showing absent MSH2 and MSH6 staining on IHC (Bauer CM et al. Fam. Cancer 2011 Mar;10:37-42; Walsh MD et al. Clin. Cancer Res. 2010 Apr;16:2214-24). 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.
Color Diagnostics, LLC DBA Color Health	RCV000491995	SCV000690016	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-25	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with Lynch syndrome-associated cancer (PMID: 10404063, 10777691, 12414824, 15655560, 15713769, 15849733, 16311127, 16451135, 18759827, 19698169, 19706203, 20215533, 20587412, 20872076, 24278394, 28449805). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115505	SCV000889424	pathogenic	not provided	2022-03-03	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the MSH2 mRNA and causes the premature termination of MSH2 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 Lynch syndrome (PMIDs: 34178123 (2021), 28874130 (2017), 28449805 (2017), 24278394 (2013), 20587412 (2010), 20007843 (2010), 19698169 (2009), 18759827 (2008), 15849733 (2005), 10777691 (2000)), breast cancer (PMIDs: 20215533 (2010), 16311127 (2005)), endometrial cancer (PMID: 15655560 (2005)), prostate cancer (PMID: 20872076 (2011)), and urinary tract cancer (PMID: 31615790 (2020)). Based on the available information, this variant is classified as pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000409229	SCV001499737	pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409229	SCV004018429	pathogenic	Lynch syndrome 1	2023-03-24	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	RCV000409229	SCV004196864	pathogenic	Lynch syndrome 1	2023-03-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000115505	SCV000592517	uncertain significance	not provided		no assertion criteria provided	clinical testing