Submissions for variant NM_000251.3(MSH2):c.388_389del (p.Gln130fs)

dbSNP: rs63750704

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076592	SCV000107625	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000163755	SCV000214332	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	clinical testing	The c.388_389delCA pathogenic mutation, located in coding exon 3 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 388 to 389, causing a translational frameshift with a predicted alternate stop codon (p.Q130Vfs*2). This alteration has been detected in several Lynch Syndrome families (Mangold E et al. Int J Cancer. 2005 Sep 20;116(5):692-702; Walsh MD et al. Mod Pathol. 2012 May;25(5):722-30; Naseem H et al. Clin Genet. 2006 Nov;70(5):388-95; Maia S et al. Fam. Cancer 2016 Jan; 15(1):111-21). Additionally, this alteration has been identified multiple individuals with MSI-H colorectal cancer (CRC) tumors lacking MSH2 on IHC (Vaccaro CA et al. Dis Colon Rectum. 2007 Oct;50(10):1604-11; Barnetson RA et al. N Engl J Med. 2006 Jun 29; 354(26):2751-63) and in an individual diagnosed with gastric cancer (Vidal AF et al. BMC Cancer, 2021 Apr;21:363). This alteration was reported as a Portuguese founder mutation after it was detected in 16 unrelated Portuguese HNPCC families that met either Amsterdam or Bethesda criteria (Pinheiro M et al. Clin Genet. 2013 Sep;84(3):244-50). 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.
GeneDx	RCV000235890	SCV000293505	pathogenic	not provided	2019-07-01	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; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28932927, 22480969, 16216036, 16341804, 24344984, 23170986, 26289772, 29575718, 15849733, 22322191, 21642682, 27007491, 33258288)
Color Diagnostics, LLC DBA Color Health	RCV000163755	SCV000690106	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-17	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 observed in multiple individuals and families affected with Lynch syndrome-associated cancer (PMID: 15849733, 21642682, 22322191, 22480969, 23170986, 24344984, 28874130), and an individual from a family affected with Lynch syndrome who was affected with prostate cancer that demonstrated loss of MSH2 protein via immunohistochemistry analysis (PMID: 26289772). Haplotype analysis suggests that this is a founder mutation in the Portuguese population (PMID: 23170986). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076592	SCV000917697	pathogenic	Lynch syndrome	2018-05-10	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.388_389delCA (p.Gln130ValfsX2) 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 (eg. c.528_529delTG, p.Cys176X; c.704_705delAA, p.Lys235fsX20). The variant was absent in 121404 control chromosomes. c.388_389delCA has been reported in the literature in multiple individuals affected with Lynch Syndrome. The variant was reported as a founder mutation in Portuguese Lynch syndrome families (Pinheiro_2013). 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.
Invitae	RCV000816977	SCV000957509	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-29	criteria provided, single submitter	clinical testing	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 individual(s) with Lynch syndrome (PMID: 15849733, 23170986, 24344984). It is commonly reported in individuals of Portuguese ancestry (PMID: 15849733, 23170986, 24344984). ClinVar contains an entry for this variant (Variation ID: 91090). For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137613	SCV003806802	pathogenic	Muir-Torré syndrome	2022-12-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated
PreventionGenetics, part of Exact Sciences	RCV004528277	SCV004111545	pathogenic	MSH2-related disorder	2023-05-02	criteria provided, single submitter	clinical testing	The MSH2 c.388_389delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln130Valfs*2). This variant was reported in multiple individuals/families with hereditary nonpolyposis colorectal cancer (Mangold et al. 2005. PubMed ID: 15849733, Pinheiro et al. 2013. PubMed ID: 23170986, Schneider et al. 2018. PubMed ID: 29575718, Soares et al. 2018. PubMed ID: 28932927). This variant has been establish as a founder mutation in Portuguese Lynch syndrome families (Pinheiro et al. 2013. PubMed ID: 23170986). This variant is classified as Pathogenic in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/91090/) and has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in MSH2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV000087058	SCV004188033	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.
Baylor Genetics	RCV000087058	SCV004196868	pathogenic	Lynch syndrome 1	2023-02-08	criteria provided, single submitter	clinical testing
OMIM	RCV000087058	SCV000119872	pathogenic	Lynch syndrome 1	2013-09-01	no assertion criteria provided	literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000235890	SCV001799737	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000235890	SCV001973455	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000087058	SCV002054066	not provided	Lynch syndrome 1		no assertion provided	literature only