Submissions for variant NM_000251.3(MSH2):c.1204del (p.Gln402fs)

dbSNP: rs63751413

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076062	SCV000107076	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing a premature termination codon
Ambry Genetics	RCV000491476	SCV000580641	pathogenic	Hereditary cancer-predisposing syndrome	2018-05-17	criteria provided, single submitter	clinical testing	The c.1204delC pathogenic mutation, located in coding exon 7 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 1204, causing a translational frameshift with a predicted alternate stop codon (p.Q402Kfs*10). This alteration has been reported in several Scandinavian families with HNPCC/Lynch syndrome (Nilbert M et al. Fam. Cancer 2009 Jun; 8(1):75-83; Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85; Lagerstedt-Robinson K. et al. Oncol. Rep. 2016 Nov;36(5):2823-2835). 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.
Invitae	RCV000684857	SCV000812317	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-09-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln402Lysfs*10) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has been observed in families suspected of Lynch syndrome (PMID: 18566915, 20587412, 27601186). ClinVar contains an entry for this variant (Variation ID: 90566). This variant is not present in population databases (ExAC no frequency).
Myriad Genetics, Inc.	RCV003452808	SCV004186813	pathogenic	Lynch syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076062	SCV004848356	pathogenic	Lynch syndrome	2020-05-13	criteria provided, single submitter	clinical testing	The p.Gln402LysfsX10 variant in MSH2 has been reported in four individuals with Lynch syndrome (Nilbert 2009, Sjursen 2010, Lagerstedt-Robinson 2016). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 90566). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 402 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.