Submissions for variant NM_000251.3(MSH2):c.645+2T>C

dbSNP: rs876658996

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520097	SCV000618558	likely pathogenic	not provided	2022-05-20	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of the adjacent exon; Not observed at significant frequency in large population cohorts (gnomAD); Identified in a large cohort of predominantly healthy individuals being evaluated by multi-gene panel (eMERGE Consortium 2019); This variant is associated with the following publications: (PMID: 21120944, 18822302, 31447099)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000606441	SCV000712752	pathogenic	Lynch syndrome	2016-12-21	criteria provided, single submitter	clinical testing	The c.645+2T>C variant in MSH2 has not been previously reported in individuals w ith Lynch Syndrome or in large population studies. This variant occurs in the in variant region (+/- 1,2) of the splice consensus sequence and is predicted to ca use altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the MSH2 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified a s pathogenic for Lynch syndrome in an autosomal dominant manner based upon absen ce from the general population and predicted impact to the protein.
CeGaT Center for Human Genetics Tuebingen	RCV000520097	SCV001249230	pathogenic	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV001378494	SCV001576071	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the MSH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16884359). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 450032). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002367733	SCV002656812	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-26	criteria provided, single submitter	clinical testing	The c.645+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 3 in the MSH2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis for this alteration is inconclusive; however, RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.