Submissions for variant NM_000251.3(MSH2):c.1700_1704del (p.Lys567fs)

dbSNP: rs63750474

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076252	SCV000107271	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV002228183	SCV000548263	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-01-09	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: 90755). This variant is also known as 1699delAAACA and 1700-4del. This premature translational stop signal has been observed in individual(s) with Lynch syndrome or Muir-Torre syndrome (PMID: 8931714, 11208710, 11606497). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys567Argfs*3) 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).
GeneDx	RCV000483742	SCV000565803	pathogenic	not provided	2015-03-16	criteria provided, single submitter	clinical testing	This deletion of 5 nucleotides in MSH2 is denoted c.1700_1704delAAACA at the cDNA level and p.Lys567ArgfsX3 (K567RfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AATA[AAACA]GAAT. The deletion causes a frameshift, which changes a Lysine to an Arginine at codon 567, and creates a premature stop codon at position 3 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 Lys567ArgfsX3 has been observed in at least one family presenting with the Muir-Torre variant of Lynch syndrome (Kruse 1996, Mangold 2004). we consider this variant to be pathogenic.
Ambry Genetics	RCV000490820	SCV000580459	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-08	criteria provided, single submitter	clinical testing	The c.1700_1704delAAACA pathogenic mutation, located in coding exon 11 of the MSH2 gene, results from a deletion of 5 nucleotides at nucleotide positions 1700 to 1704, causing a translational frameshift with a predicted alternate stop codon (p.K567Rfs*3). This mutation has been reported in multiple individuals diagnosed with MSH2-deficient and/or microsatellite unstable colorectal cancer (Terdiman et al. Gastroenterology. 2001 Jan;120(1):21-30; Samowitz WS et al. Gastroenterology. 2001 Oct;121:830-8; Ambry internal data), as well as in an individual diagnosed with Muir-Torre syndrome (Mangold E et al. J Med Genet. 2004 Jul;41(7):567-72). Of note, this mutation is also designated as 1699del5 and 1700-4del in published 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.	RCV003452852	SCV004188968	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.