Submissions for variant NM_000251.3(MSH2):c.2502_2508del (p.Asn835fs)

dbSNP: rs63751447

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076489	SCV000107518	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000163822	SCV000214407	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-22	criteria provided, single submitter	clinical testing	The c.2502_2508delTAATTTC pathogenic mutation, located in coding exon 15 of the MSH2 gene, results from a deletion of 7 nucleotides at nucleotide positions 2502 to 2508, causing a translational frameshift with a predicted alternate stop codon (p.N835Lfs*4). This mutation has been reported in multiple individuals with Lynch syndrome-associated cancers, several whose families met Amsterdam or Bethesda criteria and whose tumors showed high microsatellite instability and/or absent MSH2 staining on IHC (Scott RJ et al. Am. J. Hum. Genet., 2001 Jan;68:118-127; Coleman MG et al. Br. J. Cancer, 2001 Nov;85:1486-91; Ward R et al. J. Cancer Res. Clin. Oncol., 2002 Aug;128:403-11; Pigatto F et al. Hered Cancer Clin Pract, 2004 Nov;2:175-84; Chubb D et al. Nat Commun, 2016 06;7:11883; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199). 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	RCV000202117	SCV000568055	pathogenic	not provided	2022-03-23	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Scott 2001, Sjursen 2016); 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: 24307375, 28152038, 11112663, 22949379, 25248401, 27064304, 30322717, 31615790)
Invitae	RCV001051236	SCV001215380	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn835Leufs*4) 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 clinical features of Lynch syndrome (PMID: 11112663, 12200596). ClinVar contains an entry for this variant (Variation ID: 90987). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824598	SCV002074360	pathogenic	Hereditary nonpolyposis colon cancer	2022-01-20	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2502_2508delTAATTTC (p.Asn835LeufsX4) 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 was absent in 251436 control chromosomes. c.2502_2508delTAATTTC has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer and related cancers (examples: Ward_2002, Guindalini_2015, Wischhusen_2020). 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. Three 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.
Myriad Genetics, Inc.	RCV003452916	SCV004188062	pathogenic	Lynch syndrome 1	2023-08-09	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	RCV003452916	SCV004196893	pathogenic	Lynch syndrome 1	2022-10-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163822	SCV004356744	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	This variant deletes 7 nucleotides in exon 15 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: 11112663, 11720433, 12200596, 26248088). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202117	SCV000257179	likely pathogenic	not provided		no assertion criteria provided	research