Submissions for variant NM_000251.3(MSH2):c.2005+8dup

dbSNP: rs267607992

Total submissions: 9

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524370	SCV000284130	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000410189	SCV000488565	likely benign	Lynch syndrome 1	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 Diagnostics, LLC DBA Color Health	RCV000128999	SCV000684996	benign	Hereditary cancer-predisposing syndrome	2016-10-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000410189	SCV001135747	likely benign	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410189	SCV004018381	benign	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
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.