Submissions for variant NM_000251.3(MSH2):c.387_388del (p.Gln130fs)

dbSNP: rs63750924

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076591	SCV000107624	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000684791	SCV000255276	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-17	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: 91089). This variant is also known as 129delTC or c.388_389delTC. This premature translational stop signal has been observed in individuals with Lynch syndrome (PMID: 8592341, 10375096, 12658575, 15849733, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln130Valfs*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).
GeneDx	RCV000202145	SCV000292615	pathogenic	not provided	2015-09-16	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides in MSH2 is denoted c.387_388delTC at the cDNA level and p.Gln130ValfsX2 (Q130VfsX2) at the protein level. The normal sequence, with the bases that are deleted in braces, is TCTC[TC]AGTT. The deletion causes a frameshift, which changes a Glutamine to a Valine at codon 130, 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.387_388delTC, also known as 129delTC or c.388_389delTC using alternative nomenclature, has been observed in several individuals with personal and/or family histories consistent with Lynch syndrome (Buerstedde 1995, Wagner 2003, Mangold 2005). We consider this variant to be pathogenic.
Ambry Genetics	RCV000491648	SCV000580392	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-14	criteria provided, single submitter	clinical testing	The c.387_388delTC pathogenic mutation, located in coding exon 3 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 387 to 388, causing a translational frameshift with a predicted alternate stop codon (p.Q130Vfs*2). One study identified three individuals heterozygous for this mutation in a Swiss HNPCC family: an individual diagnosed with colon cancer at age 57, an individual diagnosed with rectal cancer at age 46 who was also reported to have several adenomas of the colon, and an individual diagnosed with cancers of the nasopharynx and colon at ages 24 and 43, respectively. Furthermore, one untested obligate carrier in the family was reported to have a glioblastoma multiforme consistent with Turcot's syndrome (Buerstedde JM et al. J. Med. Genet. 1995 Nov;32(11):909-12). An additional study identified this mutation in a single individual with demonstrated absence of MSH2 protein on immunohistochemistry and low microsatellite instability on tumor testing (Lamberti C et al. Digestion 2006;74:58-67). This alteration was reported somatically in a sebaceous neoplasm with absent MSH2 and MSH6 protein (Joly MO et al. Hum. Mutat. 2015 Mar;36:292-5). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202145	SCV000601476	pathogenic	not provided	2015-09-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000202145	SCV002047951	pathogenic	not provided	2021-04-06	criteria provided, single submitter	clinical testing	The MSH2 c.387_388delTC; p.Gln130ValfsTer2variant (rs63750924) is reported in the literature in several individuals affected with hereditary nonpolyposis colorectal cancer (Buerstedde 1995, Carter 2018, Lamberti 2006, Mangold 2005). This variant is also reported in ClinVar (Variation ID: 91089), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References Buerstedde et al. Detection of new mutations in six out of 10 Swiss HNPCC families by genomic sequencing of the hMSH2 and hMLH1 genes. J Med Genet. 1995 Nov;32(11):909-12. PMID: 8592341. Carter et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol 2018 Dec;151(3):481-488. PMID: 30322717. Lamberti C et al. Frequency of hereditary non-polyposis colorectal cancer among unselected patients with colorectal cancer in Germany. Digestion. 2006;74(1):58-67. PMID: 17095871. Mangold E et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005 Sep 20;116(5):692-702. PMID: 15849733.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003313934	SCV004013450	pathogenic	Familial cancer of breast	2023-07-18	criteria provided, single submitter	clinical testing	A known pathogenic mutation was detected in the MSH2 gene (c.387_388delTC). This sequence change creates a premature translational stop signal (p.Gln130Valfs*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 individuals with Lynch syndrome (PMID: 8592341, 10375096, 12658575, 15849733, 28514183). This variant is also known as 129delTC or c.388_389delTC. ClinVar contains an entry for this variant (Variation ID: 91089). For these reasons, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic mutations in the MSH2 gene are associated with hereditary nonpolyposis colorectal cancer syndrome, also known as Lynch syndrome.
Myriad Genetics, Inc.	RCV003452938	SCV004188005	pathogenic	Lynch syndrome 1	2023-07-27	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202145	SCV000257188	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353820	SCV000592464	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001250035	SCV001423960	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing