Submissions for variant NM_000251.3(MSH2):c.1552_1553del (p.Gln518fs)

dbSNP: rs63749930

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076193	SCV000107209	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000235817	SCV000293508	pathogenic	not provided	2019-04-19	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: 10495924, 10564582, 8776590, 18307539, 9611074, 18550572, 10200055, 11304573, 11306449, 14574010, 14961575)
Invitae	RCV000707356	SCV000836450	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln518Valfs*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 hereditary non-polyposis colorectal cancer (PMID: 8776590, 11304573, 11306449, 14961575, 18307539). This variant is also known as MSH2 c.1550_1551delCA. ClinVar contains an entry for this variant (Variation ID: 90697). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235817	SCV001134340	pathogenic	not provided	2019-02-12	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Color Diagnostics, LLC DBA Color Health	RCV001187673	SCV001354535	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 10 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. This variant has been identified in multiple individuals and families affected with Lynch syndrome (PMID: 8776590, 11304573, 11306449, 14961575, 18307539). 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.
Ambry Genetics	RCV001187673	SCV002707477	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-28	criteria provided, single submitter	clinical testing	The c.1552_1553delCA pathogenic mutation, located in coding exon 10 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 1552 to 1553, causing a translational frameshift with a predicted alternate stop codon (p.Q518Vfs*10). This alteration has been identified in multiple unrelated patients and families with HNPCC/Lynch syndrome cancers, including colorectal, endometrial, and pancreatic (Nyström-Lahti M et al. Hum. Mol. Genet., 1996 Jun;5:763-9; Cederquist K et al. Int. J. Cancer, 2004 Apr;109:370-6; Yan HL et al. Cancer Sci., 2008 Apr;99:770-80). Of note, this alteration is also designated as c.1550delCA and c.1550_1551delCA 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.
Myriad Genetics, Inc.	RCV003452841	SCV004187987	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.
Baylor Genetics	RCV003452841	SCV004196182	pathogenic	Lynch syndrome 1	2023-10-17	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353393	SCV000592506	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Gln518ValfsX10 variant was identified in 14 of 1078 proband chromosomes (frequency: 0.013) from individuals or families with colorectal cancer (Cederquist 2004, Gylling 2008, Nystrom-Lahti 1996, Renkonen 2004, Salahshor 2001, Schweizer 2001, Yan 2008). The variant was also identified in dbSNP (ID: rs63749930) “With Pathogenic allele”, HGMD, COSMIC, “Mismatch Repair Genes Variant Database” and the ClinVar database (classified as a pathogenic variant by the InSiGHT). The p.Gln518ValfsX10 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 518 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. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.