Submissions for variant NM_000251.3(MSH2):c.1457_1460del (p.Asn486fs)

dbSNP: rs1114167806

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076166	SCV000107183	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000166117	SCV000216887	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-09	criteria provided, single submitter	clinical testing	The c.1457_1460delATGA pathogenic mutation, located in coding exon 9 of the MSH2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1457 to 1460, causing a translational frameshift with a predicted alternate stop codon (p.N486Tfs*10). This alteration has also been reported in multiple individuals with personal and/or family history consistent with Lynch syndrome and is described in the literature as a Chinese founder mutation (Chan TL et al, J. Natl. Cancer Inst. 1999 Jul; 91(14):1221-6; Yuen ST et al, Oncogene 2002 Oct; 21(49):7585-92; Chan TL et al, Am. J. Hum. Genet. 2004 May; 74(5):1035-42; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Sheng JQ et al. Chin J Dig Dis, 2006;7:197-205; Cruz-Correa M et al. Fam Cancer, 2015 Sep;14:415-25; Meric-Bernstam F et al. Ann. Oncol. 2016 May;27(5):795-800; Rossi BM et al. BMC Cancer 2017 Sep;17(1):623; Sunga AY et al. Cancer Genet, 2017 04;212-213:1-7; Zhang J et al. Oncotarget, 2017 Apr;8:24533-24547; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). Additionally, this alteration was identified in multiple patients with breast and/or ovarian cancer (Kwong A et al. J Mol Diagn, 2020 04;22:544-554). Of note, this alteration is also designated as c.1452_1455delAATG and c.1457del4 in published literature. 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	RCV000236889	SCV000293152	pathogenic	not provided	2022-07-27	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 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: 25345868, 24710284, 15516845, 12386821, 24307375, 26787237, 15042510, 10413423, 32068069, 28874130, 28449805, 30730459, 31830689, 30521064, 28445943)
3DMed Clinical Laboratory Inc	RCV000677889	SCV000804050	pathogenic	Carcinoma of colon	2017-08-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166117	SCV000911928	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-30	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 9 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: 10413423, 12386821, 15042510, 25782445, 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.
Academic Department of Medical Genetics, University of Cambridge	RCV000166117	SCV000992192	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-26	criteria provided, single submitter	research	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Invitae	RCV001201896	SCV001372987	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn486Thrfs*10) 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: 10413423, 28449805, 28874130). This variant is also known as c.1452_1455delAATG. ClinVar contains an entry for this variant (Variation ID: 90670). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000001842	SCV004188021	pathogenic	Lynch syndrome 1	2023-08-02	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
OMIM	RCV000001842	SCV000021998	pathogenic	Lynch syndrome 1	2004-05-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000677889	SCV000592503	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Asn486ThrfsX10 variant was identified in 9 of 598 proband chromosomes (frequency: 0.015) from Asian individuals or families with colorectal cancer (Chan 1999, Chan 2004, Yuen 2002), and was not identified in 210 control chromosomes from healthy individuals (Chan 1999).The variant was also identified in dbSNP (ID: rs63750148), HGMD, “InSiGHT Colon Cancer Database” and the ClinVar database (classified as a pathogenic variant). The p.Asn486ThrfsX10 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 486 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. Two studies have suggested that p.Asn486ThrfsX10 variant is a founder mutation and is common in the southern Chinese population (Chan 2004, Yuen 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
3DMed Clinical Laboratory Inc	RCV000677888	SCV000804049	pathogenic	Colon cancer	2017-08-03	no assertion criteria provided	clinical testing
GeneReviews	RCV000001842	SCV002054077	not provided	Lynch syndrome 1		no assertion provided	literature only