Submissions for variant NM_000251.3(MSH2):c.478C>T (p.Gln160Ter)

dbSNP: rs63751426

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076606	SCV000107642	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000547313	SCV000625429	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-01-05	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). 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 reported in an individual affected with Muir-Torre syndrome (PMID: 15235030). ClinVar contains an entry for this variant (Variation ID: 91103). This sequence change creates a premature translational stop signal (p.Gln160*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532993	SCV001748828	pathogenic	Hereditary nonpolyposis colon cancer	2021-06-24	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.478C>T (p.Gln160X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251476 control chromosomes (gnomAD). c.478C>T has been reported in the literature in individuals affected with Muir-Torre syndrome or Lynch syndrome (Mangold_2004, Bonadona_2011, Cornejo_2014, Wischhusen_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002336226	SCV002640100	pathogenic	Hereditary cancer-predisposing syndrome	2018-03-08	criteria provided, single submitter	clinical testing	The p.Q160* pathogenic mutation (also known as c.478C>T), located in coding exon 3 of the MSH2 gene, results from a C to T substitution at nucleotide position 478. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation was identified in a patient with Muir-Torre syndrome (Mangold E et al. J. Med. Genet., 2004 Jul;41:567-72). 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.	RCV003452943	SCV004187990	pathogenic	Lynch syndrome 1	2023-07-27	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001250038	SCV001423963	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing