ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.792+1del (rs1064794155)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485573 SCV000568005 pathogenic not provided 2015-09-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH2 c.792+1delG or IVS4+1delG and consists of a single nucleotide deletion at the +1 position of intron 4 of the MSH2 gene. The 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. This variant has not, to our knowledge, been published in the literature. Based on the current evidence, we consider MSH2 c.792+1delG to be pathogenic.
Ambry Genetics RCV000491720 SCV000580478 pathogenic Hereditary cancer-predisposing syndrome 2016-01-21 criteria provided, single submitter clinical testing Thec.792+1delGpathogenicmutation,results from a deletion ofthe first nucleotide downstream of codingexon4 in theMSH2gene. A different alteration impacting thesame position, c.792+1G>A, has been identified in afamily meeting Amsterdam I criteriawith tumors exhibiting loss of MSH2 and MSH6 on IHC (Casey G et al., JAMA. 2005; 293(7): 799-809).Using the BDGP and ESEfinder splice site prediction tools, the c.792+1delGalteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable.Alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007.Genet Med.2008;10:294).
Invitae RCV000525827 SCV000625463 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2017-06-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827).  ClinVar contains an entry for this variant (Variation ID: 419862). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174984 SCV001338474 likely pathogenic Lynch syndrome 2020-04-16 criteria provided, single submitter clinical testing Variant summary: MSH2 c.792+1delG 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 250880 control chromosomes. To our knowledge, no occurrence of c.792+1delG in individuals affected with Hereditary Nonpolyposis Colorectal Cancer has been reported in the literature and no experimental evidence demonstrating its impact on protein function have been reported. However, the variant has been reported in inviduals in the UMD database. Three 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.

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