Submissions for variant NM_000251.3(MSH2):c.1853del (p.Pro618fs)

dbSNP: rs267607984

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076301	SCV000107322	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000481856	SCV000566069	pathogenic	not provided	2015-03-26	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in MSH2 is denoted c.1853delC at the cDNA level and p.Pro618HisfsX17 (P618HfsX17) at the protein level. The normal sequence, with the base that is deleted in brackets, is GTTC[C]ATAT. The deletion causes a frameshift, which changes a Proline to a Histidine at codon 618, and creates a premature stop codon at position 17 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.1853delC has been observed in association with colorectal cancer (Kovac 2011). we consider this variant to be pathogenic.
Invitae	RCV001854318	SCV002228907	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-17	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: 90800). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18772310, 21671081). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro618Hisfs*17) 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).
Ambry Genetics	RCV002408596	SCV002711544	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	clinical testing	The c.1853delC pathogenic mutation, located in coding exon 12 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 1853, causing a translational frameshift with a predicted alternate stop codon (p.P618Hfs*17). This mutation has been reported in multiple individuals with Lynch syndrome (Bujalkova M et al. Clin. Chem. 2008 Nov;54(11):1844-54; Kovac M et al. Fam. Cancer 2011 Sep;10(3):605-16; Goodfellow PJ et al. J. Clin. Oncol., 2015 Dec;33:4301-8). In addition to the information 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.	RCV003452861	SCV004187951	pathogenic	Lynch syndrome 1	2023-08-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
CZECANCA consortium	RCV001270945	SCV001451749	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing