Submissions for variant NM_000251.3(MSH2):c.943-2A>G

dbSNP: rs587779198

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076759	SCV000107800	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000491601	SCV000580627	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	clinical testing	The c.943-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides before coding exon 6 in the MSH2 gene. This variant has been reported in an individual meeting Amsterdam criteria whose colorectal tumor exhibited loss of MSH2 and MSH6 protein on immunohistochemistry (Ambry internal data). This variant has also been reported in a 44 year old male diagnosed with colorectal cancer exhibiting loss of MSH2 and MSH6 protein on immunohistochemistry (Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (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	RCV000544929	SCV000625486	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-08	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 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 Lynch syndrome (PMID: 11151427, 21520333; Invitae). ClinVar contains an entry for this variant (Variation ID: 91254). 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.
Counsyl	RCV000663253	SCV000786478	likely pathogenic	Lynch syndrome 1	2018-05-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280659	SCV001467944	likely pathogenic	Hereditary nonpolyposis colon cancer	2020-12-11	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.943-2A>G 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 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251250 control chromosomes. c.943-2A>G has been reported in the literature in an individual affected with Hereditary Nonpolyposis Colorectal Cancer (Jiang_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491601	SCV002052446	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-19	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 5 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer whose tumor exhibited the loss of MSH2/MSH6 proteins by immunohistochemistry (PMID: 30521064) and different canonical splice site variants at this splice acceptor site have also been reported in individuals suspected of Lynch syndrome (PMID: 11151427, 15849733, 20233461, 26866578, 28874130). 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.	RCV000663253	SCV004018335	pathogenic	Lynch syndrome 1	2023-12-13	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].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353928	SCV000592481	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 c.943-2A>G variant was not identified in the literature. The variant was identified in the InSiGHT Colon Cancer Gene Variant Database (2X as “likely pathogenic”) and the ClinVar database (classified as a “likely pathogenic” variant by inSIGHT). The variant was not identified in any of the following databases: dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “Zhejiang Colon Cancer Database”, GeneInsight VariantWire database, and UMD. The c.943-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.