Submissions for variant NM_000251.2(MSH2):c.2595_2597del (p.Ile865del) (rs759912716)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479072	SCV000570479	uncertain significance	not provided	2016-06-02	criteria provided, single submitter	clinical testing	This in-frame deletion of 3 nucleotides in MSH2 is denoted c.2595_2597delCAT at the cDNA level and p.Ile865del (I865del) at the protein level. The normal sequence, with the bases that are deleted in braces, is ATAT[CAT]GGAA. This deletion of a single Isoleucine residue occurs at a position that is not conserved and is located in the helix-turn-helix domain (Lutzen 2008). This variant was observed in at least one family who meets Amsterdam II criteria for Lynch syndrome; however, this family was also found to carry a pathogenic variant in MLH1 (Kamiza 2015). Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear. We consider MSH2 Ile865del to be a variant of uncertain significance.
Invitae	RCV000630027	SCV000750983	uncertain significance	Hereditary nonpolyposis colon cancer	2018-11-19	criteria provided, single submitter	clinical testing	This variant, c.2595_2597delCAT, results in the deletion of 1 amino acid(s) of the MSH2 protein (p.Ile865del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in a family affected with Lynch syndrome (PMID: 26053027). However, in that family a pathogenic allele was also identified in MLH1, which suggests that this c.2595_2597delCAT variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 421318). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.