Submissions for variant NM_000251.3(MSH2):c.561_569del (p.Glu188_Leu190del)

dbSNP: rs63750088

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076640	SCV000107675	pathogenic	Lynch syndrome	2014-10-10	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199286	SCV001370363	pathogenic	Mismatch repair cancer syndrome 1	2019-05-04	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM4.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310203	SCV001499804	likely pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
Invitae	RCV001854332	SCV002236749	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-09-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 91136). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 9748699, 10970186). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This variant, c.561_569del, results in the deletion of 3 amino acid(s) of the MSH2 protein (p.Glu188_Leu190del), but otherwise preserves the integrity of the reading frame.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281912	SCV002571898	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-08-09	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.561_569delTGAGGCTCT (p.Glu188_Leu190del) results in an in-frame deletion that is predicted to remove 3 amino acids from the encoded protein. The variant was absent in 251480 control chromosomes (gnomAD). c.561_569delTGAGGCTCT has been reported in the literature in an extended HNPCC family with multiple affected members and was shown to co-segregate with disease (Ravnik-Glavac_1998, 2000). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.