Submissions for variant NM_006231.4(POLE):c.6682_6684del (p.Lys2228del)

dbSNP: rs878854896

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000759318	SCV000289477	uncertain significance	not provided	2025-01-20	criteria provided, single submitter	clinical testing	This variant, c.6682_6684del, results in the deletion of 1 amino acid(s) of the POLE protein (p.Lys2228del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 240613). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant 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.
Counsyl	RCV000233239	SCV000489039	uncertain significance	Colorectal cancer, susceptibility to, 12	2016-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000759318	SCV000572162	uncertain significance	not provided	2025-02-21	criteria provided, single submitter	clinical testing	Observed in an individual with endometrial cancer (PMID: 31837202); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30640733, 29056344, 19296856, 31837202)
Ambry Genetics	RCV000565528	SCV000671407	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-07	criteria provided, single submitter	clinical testing	The c.6682_6684delAAG variant (also known as p.K2228del) is located in coding exon 48 of the POLE gene. This variant results from an in-frame AAG deletion at nucleotide positions 6682 to 6684. This results in the in-frame deletion of a lysine at codon 2228. This amino acid position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759318	SCV000888572	uncertain significance	not provided	2019-12-13	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000565528	SCV000886716	uncertain significance	Hereditary cancer-predisposing syndrome	2018-11-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532936	SCV004727486	uncertain significance	POLE-related disorder	2024-01-13	no assertion criteria provided	clinical testing	The POLE c.6682_6684delAAG variant is predicted to result in an in-frame deletion (p.Lys2228del). This variant has been reported in an individual with endometrial cancer (Lin et al. 2019. PubMed ID: 31837202). However, this individual also harbored a pathogenic variant in the SMAD4 gene. This variant has not been reported in a large population database. In ClinVar, this variant is interpreted as uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/240613/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.