Submissions for variant NM_000251.3(MSH2):c.366+1G>A

dbSNP: rs267607924

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236788	SCV000293166	pathogenic	not provided	2018-03-29	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH2 c.366+1G>A or IVS2+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 2 of the MSH2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. While splicing based functional assays have not been completed for this specific variant, a similar variant involving the same nucleotide, MSH2 c.366+1G>T, has been reportedly confirmed to result in skipping of exon 2 via RT-PCR (Auclair 2006). This variant has been reported in at least two individuals with Lynch syndrome (Geary 2008, Sjursen 2016). Based on current evidence, we consider MSH2 c.366+1G>A to be pathogenic.
Invitae	RCV000791394	SCV000548172	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-21	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 245947). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 17939062, 25430799, 27064304; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526857	SCV000696262	pathogenic	Hereditary nonpolyposis colon cancer	2021-06-01	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.366+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250038 control chromosomes. c.366+1G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome (Geary_2008, Goldberg_2014, Sjursen_2016). The variant has also been reported as a somatic occurrence in the MMR deficient tumor of a 71-year old female who was indicated to harbor another potentially pathogenic MSH2 variant, c.1738G>T (p.Glu580X) presumably due to LOH (Haraldsdottir_2014). This individual had previously tested negative for MMR germline mutations by Sanger sequencing, MLPA, and MLH1 hypermethylation and did not fulfill the Amsterdam-II or the revised Bethesda criteria for Lynch syndrome. These data indicate that the variant is very likely to be associated with disease in both germline and somatic settings. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000471120	SCV000887346	pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.366+1G>A has a 99.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics	RCV001020825	SCV001182356	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-18	criteria provided, single submitter	clinical testing	The c.366+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the MSH2 gene. This alteration has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families to date (Geary J et al. Fam. Cancer. 2008 Oct;7:163-72; Goldberg Y et al. Clin. Genet. 2015 Jun;87:549-53; Sjursen W et al. Mol. Genet. Genomic Med. 2016 Mar;4:223-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001020825	SCV001354851	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-06-01	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 2 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-associated cancers (PMID: 17939062, 27064304, 25430799). 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.
Myriad Genetics, Inc.	RCV003454715	SCV004186714	likely pathogenic	Lynch syndrome 1	2023-07-27	criteria provided, single submitter	clinical testing	This variant is considered likely 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.