Submissions for variant NM_000251.3(MSH2):c.1609A>T (p.Lys537Ter)

dbSNP: rs980244810

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193244	SCV001361972	pathogenic	Hereditary nonpolyposis colon cancer	2019-02-12	criteria provided, single submitter	clinical testing	Variant summary: The variant, MSH2 c.1609A>T (p.Lys537X) 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 (eg. c.1684G>T(p.Glu562X), c.1777C>T(p.Gln593X) ). The variant was absent in 246172 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with HNPCC (hereditary nonpolyposis colorectal cancer) and ovarian cancer (Nilbert_2009, Bernards_2016, Sjursen_2015) . 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002393445	SCV002703698	pathogenic	Hereditary cancer-predisposing syndrome	2019-01-09	criteria provided, single submitter	clinical testing	The p.K537* pathogenic mutation (also known as c.1609A>T), located in coding exon 10 of the MSH2 gene, results from an A to T substitution at nucleotide position 1609. This changes the amino acid from a lysine to a stop codon within coding exon 10. This mutation has been reported in multiple Lynch syndrome families (Nilbert M et al. Fam Cancer. 2009;8(1):75-83; Pritchard CC et al. J Mol Diagn. 2012 Jul;14(4):357-66; Bernards SS et al. Gynecol Oncol. 2016 Feb;140(2):221-5; Sjursen W et al. Mol Genet Genomic Med. 2016 Jan 11;4(2):223-31). 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.	RCV003449627	SCV004187982	pathogenic	Lynch syndrome 1	2023-08-02	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.