Submissions for variant NM_000251.3(MSH2):c.472C>T (p.Gln158Ter)

dbSNP: rs63751226

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076605	SCV000107641	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192612	SCV001360856	pathogenic	Hereditary nonpolyposis colon cancer	2019-09-10	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.472C>T (p.Gln158X) 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 (c.811_814delTCTG, p.Ser271fsX2; c.932delA, p.Asn311ThrfsX20). The variant was absent in 251450 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with Hereditary Non-Polyposis Colon Cancer (Apessos_2005, Goldberg_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. An expert panel (InSiGHT) has classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002336225	SCV002635917	pathogenic	Hereditary cancer-predisposing syndrome	2018-11-26	criteria provided, single submitter	clinical testing	The p.Q158* pathogenic mutation (also known as c.472C>T), located in coding exon 3 of the MSH2 gene, results from a C to T substitution at nucleotide position 472. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation has been reported in a Greek family with HNPCC where the proband was diagnosed with MSI-H colorectal cancer at age 38 (Apessos A et al. Br. J. Cancer 2005 Jan;92:396-404). 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.	RCV003452942	SCV004186993	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.