ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.646-?_792+?del

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076673 SCV000107705 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research In-frame large deletion interrupting known functional domains
Invitae RCV000471152 SCV000563902 likely pathogenic Lynch syndrome 2016-09-09 criteria provided, single submitter clinical testing This variant is a gross deletion of the genomic region encompassing exon 4 of the MSH2 gene. This leads to an in-frame deletion, preserving the integrity of the reading frame. Deletions of exon 4 have been reported in multiple families affected with Lynch syndrome (PMID: 10480359, 14512394, 18566915, 19419416, 21642682). ClinVar contains an entry for a deletion of exon 4 (Variation ID: 91169). Deletion of exon 4 (p.Ile216_Gln264del) partially removes the connector domain (or DNA binding domain) of the MSH2 protein. The connector domain is required for mismatch repair (MMR) complex formation, which is necessary for adequate MSH2 mismatch repair protein function (PMID: 18822302, 18383312, 20080788, 26163658, 21454657). However, functional studies have not been performed for this particular deletion. In summary, this variant is an in-frame exonic deletion that has been seen in Lynch syndrome families and partially eliminates the MSH2 connector domain. However, in the absence of additional clinical or experimental evidence, this variant has been classified as Likely Pathogenic.

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