Submissions for variant NM_000251.3(MSH2):c.1566C>G (p.Tyr522Ter)

dbSNP: rs63750224

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076195	SCV000107212	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV001388417	SCV001589396	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-08-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr522*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15713769). ClinVar contains an entry for this variant (Variation ID: 90699). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001823110	SCV002073154	pathogenic	Lynch syndrome 1		criteria provided, single submitter	clinical testing	The stop gained p.Y522* in MSH2 (NM_000251.3) has been previously reported in affected patients (Mangold E et al, Thompson BA et al). The variant has been submitted to ClinVar as Pathogenic. The p.Y522* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002399452	SCV002709937	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-13	criteria provided, single submitter	clinical testing	The p.Y522* pathogenic mutation (also known as c.1566C>G), located in coding exon 10 of the MSH2 gene, results from a C to G substitution at nucleotide position 1566. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This alteration was identified in multiple individuals diagnosed with colorectal cancer (Casey G et al. JAMA, 2005 Feb;293:799-809; Walker M et al. Br J Surg, 2007 Dec;94:1567-71). 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.	RCV001823110	SCV004188139	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357508	SCV001552996	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH2 p.Tyr522* variant was identified in 2 of 488 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer (Thompson 2013, Walker 2007). The variant was also identified in dbSNP (ID: rs63750224) as "With Pathogenic allele", ClinVar (classified as pathogenic by an expert panel), Cosmic (1x in Lung tissue), and Insight Hereditary Tumors Database (8x as class 5). The variant was not identified in GeneInsight-COGR, UMD-LSDB, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Tyr522* variant leads to a premature stop codon at position 522, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. A functional study of the MSH2 c.1566C>G variant showed reduced expression of this allele (<90% of wild type) and the consequential loss of MSH2 and MSH6 protein expression (Casey 2005). Further, this variant was identified by our laboratory in a patient with an MSH2- and MSH6-deficient tumour. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.