Submissions for variant NM_006231.4(POLE):c.1187A>G (p.Glu396Gly)

dbSNP: rs2136008663

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002511096	SCV002260218	uncertain significance	not provided	2020-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with glycine at codon 396 of the POLE protein (p.Glu396Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLE-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV002511096	SCV002820586	uncertain significance	not provided	2022-07-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 20951805, 31829442, 26763250)
Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University School of Medicine.	RCV001543609	SCV001754759	likely pathogenic	Colorectal cancer	2021-07-19	no assertion criteria provided	research	The Glu396Gly variant in POLE has been reported in 1 Chinese family with autosomal dominant predisposition in familial colorectal cancer (CRC).