Submissions for variant NM_000251.3(MSH2):c.646-3T>G

dbSNP: rs267607930

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076666	SCV000107709	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes aberrant splicing leading to truncated protein: full inactivation of variant allele.
Color Diagnostics, LLC DBA Color Health	RCV000772131	SCV000905224	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	clinical testing	This variant causes a T to G nucleotide substitution at the -3 position of intron 3 of the MSH2 gene. Splicing studies report that this variant causes use of a cryptic splice site in intron 3 and leads to the introduction of a premature stop codon (PMID: 10693791, 11691782). This variant has been reported in individuals affected with or suspected of having Lynch syndrome (PMID: 11691782, 12658575, 16264161). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854337	SCV002269130	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 11691782, 12658575, 16264161, 31615790). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91162). Studies have shown that this variant alters MSH2 gene expression (PMID: 11691782). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000772131	SCV002660985	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-19	criteria provided, single submitter	clinical testing	The c.646-3T>G intronic pathogenic mutation results from a T to G substitution 3 nucleotides upstream from coding exon 4 in the MSH2 gene. This variant (referred to as IVS3-3T>G) has been reported in a family meeting Amsterdam I criteria (Wagner A et al. Am. J. Hum. Genet., 2003 May;72:1088-100). This variant was also identified in one of the first described HNPCC families ("Family G") in 1895 by Dr. Aldred Warthin (Lynch HT et al. Nat. Rev. Cancer, 2015 03;15:181-94). Using diploid-haploid conversion assays, this variant was shown to activate a cryptic acceptor site which results in a transcript containing a 24-base pair intronic insertion at the end of intron 3, introducing a premature stop codon (Yan H et al. Nature, 2000 Feb;403:723-4; Marra G et al. Cancer Res., 2001 Nov;61:7719-21). Functional studies demonstrated no detectable expression of MSH2 and limited expression of MSH6 by Western blotting in hybrid cell lines expressing the variant allele compared to wild type; furthermore, MMR activity for the variant was severely reduced compared to wild type (Marra G et al. Cancer Res., 2001 Nov;61:7719-21). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.