Submissions for variant NM_000251.3(MSH2):c.942+1G>T

dbSNP: rs587779193

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076752	SCV000107790	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000491583	SCV000580575	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-18	criteria provided, single submitter	clinical testing	The c.942+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 5 in the MSH2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be 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, a significant portion of the protein is affected and the impacted region is critical for protein function (Ambry internal data). This variant was identified in one Danish kindred suspicious for hereditary colorectal cancer (Nilbert M, Fam. Cancer 2009 ; 8(1):75-83). In addition, this variant has been identified in patients with Lynch syndrome associated cancers whose tumors demonstrated loss of MSH2 and MSH6 protein on IHC analysis (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 supporting evidence, this variant is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000491583	SCV000908286	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 5 of the MSH2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 18566915, 27601186). 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	RCV000816442	SCV000956952	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-08-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. 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: 18566915, 27601186). ClinVar contains an entry for this variant (Variation ID: 91247). Studies have shown that disruption of this splice site results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (internal data). This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Leu310Arg) have been determined to be pathogenic (PMID: 22290698, 30374176; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV003311677	SCV004011155	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	MSH2: PVS1, PP4:Moderate
Myriad Genetics, Inc.	RCV003452976	SCV004188972	pathogenic	Lynch syndrome 1	2023-07-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. Functional studies indicate this variant impacts protein function [PMID: 8062247].
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076752	SCV004848285	likely pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The c.942+1G>T variant in MSH2 has been reported in 1 individual affected with Lynch syndrome (Nilbert 2009) and was absent from large population studies. This variant was classified as Likely Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 91247). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MSH2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. Other variants affecting the same splice site have been reported in ClinVar (Pathogenic or Likely Pathogenic). In summary, the c.942+1G>T variant meets criteria to be classified as pathogenic for Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PM5.