Submissions for variant NM_000251.3(MSH2):c.528_529del (p.Cys176_Glu177delinsTer)

dbSNP: rs587779164

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076630	SCV000107665	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000220739	SCV000278274	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-27	criteria provided, single submitter	clinical testing	The c.528_529delTG pathogenic mutation (also known as p.C176*), located in coding exon 3 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 528 to 529. This changes the amino acid from a cysteine to a stop codon within coding exon 3. This mutation was reported in a proband from an HNPCC family whose tumor testing showed high microsatellite instability (MSI-H) (Terdiman JP et al. Gastroenterology. 2001 Jan;120(1):21-30). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076630	SCV000696274	pathogenic	Lynch syndrome	2016-03-25	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.528_529delTG (p.Cys176Terfs) variant results in premature termination at codon 176, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay, which is a commonly known mechanism for Lynch syndrome. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln344X, p.Arg383X, p.Glu569fs). Mutation Taster predicts a damaging outcome for this variant. This variant was not found in 121412 control chromosomes, but has been cited in at least 3 patients from the literature. In addition, several clinical laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000220739	SCV000905220	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-28	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 3 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 affected with Lynch syndrome (PMID: 11208710, 21642682, 26437257, 28874130). 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.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000076630	SCV000914298	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Invitae	RCV001048009	SCV001211998	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys176*) 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 or Lynch syndrome-related cancers (PMID: 11208710, 21642682, 26437257, 28874130). ClinVar contains an entry for this variant (Variation ID: 91126). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202171	SCV002774360	pathogenic	not provided	2021-06-15	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of MSH2 protein synthesis. In addition, it has been reported in families with Lynch Syndrome or Lynch Syndrome-related cancers in the published literature (PMIDs: 11208710 (2001), 21642682 (2011), 26437257 (2015), and 28874130 (2017)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003452949	SCV004187942	pathogenic	Lynch syndrome 1	2023-07-27	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV003452949	SCV004196934	pathogenic	Lynch syndrome 1	2021-09-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202171	SCV000257191	likely pathogenic	not provided		no assertion criteria provided	clinical testing