ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1076+1G>A (rs267607940)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076014 SCV000107025 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration, 2 MSI-H tumours, co-segregation with disease & MAF 0.00
Ambry Genetics RCV000132414 SCV000187506 pathogenic Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000485147 SCV000568626 pathogenic not provided 2016-05-04 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1076+1G>A or IVS6+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 6 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. Consistent with splicing predictions, this variant was observed to result in skipping of exon 6 using an RT-PCR assay (Auclair 2006). This variant has been reported in several families whose cancer histories are consistent with Lynch Syndrome (Wang 1999, Bonadona 2011, Stormorken 2005, Sjursen 2010, Mueller-Koch 2005). In addition, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000541273 SCV000625224 pathogenic Hereditary nonpolyposis colon cancer 2019-10-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 6 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 observed in two families affected with Lynch syndrome (PMID: 21642682, 15955785) and several individuals affected with colorectal or prostate cancer (PMID: 10480359, 19723918, 28449805). ClinVar contains an entry for this variant (Variation ID: 90519). An experimental study has shown that this variant leads to exclusion of exon 6 from the MSH2 transcript (PMID: 16395668). 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). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763489 SCV000894275 pathogenic Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076014 SCV001338157 pathogenic Lynch syndrome 2020-02-14 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1076+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. These predictions were confirmed by publications reporting experimental evidence demonstrating that this variant results in exon 6 skipping, which is predicted to result in a frame-shift at the protein level (Auclair_2006, Fernandez-Rozadilla_2019). The variant was absent in 251386 control chromosomes (gnomAD). The variant, c.1076+1G>A, has been reported in the literature in multiple individuals affected with Lynch Syndrome and related tumor phenotypes (e.g. Wang_1999, Fernandez-Rozadilla_2019). Four submitters, including one expert panel (InSiGHT) have provided clinical-significance assessments for this variant in ClinVar, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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