Submissions for variant NM_000251.3(MSH2):c.1077-1G>C

dbSNP: rs267607944

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076019	SCV000107040	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000491682	SCV000580498	pathogenic	Hereditary cancer-predisposing syndrome	2019-06-10	criteria provided, single submitter	clinical testing	The c.1077-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 7 of the MSH2 gene. This alteration has been reported in an individual diagnosed with colon cancer at age 36 whose tumor showed microsatellite instability and absent MSH2 staining on IHC (Canard G et al. Ann. Surg. Oncol., 2012 Mar;19:809-16). 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	RCV000491682	SCV000684902	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-04-01	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 6 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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284005	SCV001469548	pathogenic	not provided	2019-09-18	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Sema4, Sema4	RCV000491682	SCV002528806	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-11-02	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003452800	SCV004188124	pathogenic	Lynch syndrome 1	2023-07-31	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. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV003452800	SCV004196910	pathogenic	Lynch syndrome 1	2022-04-12	criteria provided, single submitter	clinical testing
GeneDx	RCV001284005	SCV005874601	pathogenic	not provided	2024-09-01	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with colorectal cancer with negative MSH2 immunohistochemistry results and present microsatellite instability (PMID: 21879275); This variant is associated with the following publications: (PMID: 27363726, 31615790, 21879275)