Submissions for variant NM_006231.4(POLE):c.2929G>A (p.Gly977Arg)

gnomAD frequency: 0.00003  dbSNP: rs142563997

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003656283	SCV001215215	uncertain significance	not provided	2023-07-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 977 of the POLE protein (p.Gly977Arg). This variant is present in population databases (rs142563997, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 34549727). ClinVar contains an entry for this variant (Variation ID: 847517). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLE protein function. 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.
Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University School of Medicine.	RCV001543611	SCV001754762	likely pathogenic	Colorectal cancer	2021-07-19	no assertion criteria provided	research	The Gly977Arg variant in POLE has been reported in 1 Chinese family with autosomal dominant predisposition in familial colorectal cancer (CRC).