Submissions for variant NM_000251.3(MSH2):c.229_230del (p.Ser77fs)

dbSNP: rs63749848

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076455	SCV000107478	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000220900	SCV000273660	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-29	criteria provided, single submitter	clinical testing	The c.229_230delAG pathogenic mutation, located in coding exon 2 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 229 to 230, causing a translational frameshift with a predicted alternate stop codon (p.S77Cfs*4). This mutation has been reported in multiple HNPCC/Lynch syndrome families in the literature (Wijnen J et al. Am. J. Hum. Genet. 1997 Aug; 61(2):329-35; Mangold E et al. Int. J. Cancer 2005 Sep;116(5):692-702; Pérez-Cabornero L et al. Eur. J. Cancer 2009 May;45(8):1485-93; Jasperson KW et al. Fam. Cancer 2010 Jun;9(2):99-107; Pérez-Cabornero L et al. J Mol Diagn 2013 May;15(3):380-90; Goodfellow PJ et al. J. Clin. Oncol. 2015 Dec;33(36):4301-8). Of note, this alteration is also designated as 229delAG and c.227_228delAG in published literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524383	SCV000284145	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-11-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser77Cysfs*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 hereditary non-polyposis colorectal cancer (PMID: 9311737, 10874307, 12414824, 15849733, 26552419). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. This variant is also known as 227-228delAG. ClinVar contains an entry for this variant (Variation ID: 90953). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194000	SCV001363216	pathogenic	Hereditary nonpolyposis colon cancer	2021-11-30	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.229_230delAG (p.Ser77CysfsX4) 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 245728 control chromosomes (gnomAD). The variant, c.229_230delAG, has been reported in the literature in multiple individuals affected with Lynch Syndrome (Wijnen_1997, Otway_2000, Wagner_2002, Mangold_2005, Goodfellow_2015, Rossi_2017). These data indicate that the variant is associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262888	SCV001440924	pathogenic	Breast carcinoma	2019-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001353711	SCV001787947	pathogenic	not provided	2023-12-12	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26552419, 12414824, 29889250, 21778331, 28874130, 34249727, 10874307, 19731080, 9311737, 15849733, 19250818, 20587412, 31054147, 31615790, 35988656, 36421850, 36457512, 32019277, 32659967)
Myriad Genetics, Inc.	RCV003452905	SCV004188003	pathogenic	Lynch syndrome 1	2023-07-26	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353711	SCV000592459	pathogenic	not provided		no assertion criteria provided	clinical testing