Submissions for variant NM_000251.3(MSH2):c.1759+1G>A

dbSNP: rs587779108

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076265	SCV000107286	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000213952	SCV000277116	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-16	criteria provided, single submitter	clinical testing	The c.1759+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the MSH2 gene. This mutation has been detected in multiple individuals with hereditary non-polyposis colorectal cancer/Lynch syndrome; several whose tumors demonstrated loss of MSH2 and MSH6 staining by immunohistochemistry (Ambry internal data). 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; however, direct evidence is insufficient at this time (Ambry internal data). 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.
Invitae	RCV000558350	SCV000625304	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 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 individuals with clinical features of Lynch syndrome (PMID: 11772966, 24728189, 28944238; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90766). 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.
Color Diagnostics, LLC DBA Color Health	RCV000213952	SCV000903298	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-03-25	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 11 of the MSH2 gene. Splice site prediction tools predict 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 colorectal cancer (PMID: 28874130, 28944238). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193999	SCV001363215	pathogenic	Hereditary nonpolyposis colon cancer	2019-03-20	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1759+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 245802 control chromosomes (gnomAD). This variant has been reported in the literature in individuals affected with Lynch Syndrome (Song_2014, Rossi_2017, DeRycke_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508076	SCV001713984	likely pathogenic	not provided	2020-12-10	criteria provided, single submitter	clinical testing	PVS1, PM2
Revvity Omics, Revvity	RCV001508076	SCV002017559	pathogenic	not provided	2019-06-04	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272054	SCV002556992	pathogenic	Lynch syndrome 1	2021-06-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001508076	SCV004220956	pathogenic	not provided	2023-06-26	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and interferes with normal MSH2 mRNA splicing. In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 28944238 (2017)) and epithelial ovarian cancer (PMID: 24728189 (2014)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.