ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2005+8dup (rs267607992)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076345 SCV000107369 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Intronic substitution with no effect on splicing tested using an NMD inhibitor
Ambry Genetics RCV000128999 SCV000172894 likely benign Hereditary cancer-predisposing syndrome 2012-08-14 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000524370 SCV000284130 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-11 criteria provided, single submitter clinical testing
Counsyl RCV000410189 SCV000488565 likely benign Lynch syndrome I 2016-05-05 criteria provided, single submitter clinical testing
GeneDx RCV000484642 SCV000565188 likely benign not specified 2017-03-30 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Health, Inc RCV000128999 SCV000684996 benign Hereditary cancer-predisposing syndrome 2016-10-07 criteria provided, single submitter clinical testing
Mendelics RCV000410189 SCV001135747 likely benign Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356833 SCV001552104 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH2 c.2005+8dupA variant was identified in 1 of 120 proband chromosomes (frequency: 0.008) from individuals or families with Lynch Syndrome (Auclair 2006, Thompson 2013). The variant was also identified in the following databases: dbSNP (ID: rs267607992) as "With Likely benign allele", ClinVar (4x likely benign, 1x benign), Clinvitae (4x likely benign), Insight Colon Cancer Gene Variant Database (2x, likely not pathogenic/little clinical significance), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (2x, germline, probably does not affect function). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, or the MMR Gene Unclassified Variants Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). Functional studies using minigene constructs and RNA extracted from lymphoblastoid cell lines showed wildtype splicing results (Auclair 2006, Thompson 2013). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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