Submissions for variant NM_006231.4(POLE):c.857C>G (p.Pro286Arg)

dbSNP: rs1057519943

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003766182	SCV000653485	uncertain significance	not provided	2017-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces proline with arginine at codon 286 of the POLE protein (p.Pro286Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in the germline of individuals with a POLE-related disease, however, it has been reported as a frequent somatic change in endometrial and colorectal cancers (PMID: 23263490, 23447401, 25224212, 24525744). This variant is located within the evolutionarily conserved exonuclease domain of the POLE protein (PMID: 23447401, 24525744). Experimental studies have shown that the P301R yeast mutant, corresponding to the p.Pro286Arg change, severely affects the fidelity rather than the proofreading function of the POLE protein, causing a strong mutator phenotype in a yeast model system (PMID: 24525744). In addition, this variant showed a reduced 3'-5' exonuclease activity compared to the wild-type protein (PMID: 25228659). In summary, this variant is a rare missense change that is not present in the population and has been shown to affect protein function. Although this variant has been found as a frequent somatic event in tumors, it has not been observed in the germline of affected individuals. In the absence of genetic and/or additional evidence, this variant has been classified as Variant of Uncertain Significance.
Database of Curated Mutations (DoCM)	RCV000443524	SCV000507146	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427424	SCV000507147	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437655	SCV000507148	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443610	SCV000507149	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426701	SCV000507150	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Oxford Haemato-Oncology Service, Oxford University Hospitals NHS Foundation Trust	RCV000626454	SCV000734844	drug response	Programmed death ligand-1 (PD-L1) blocking antibody response	2017-11-27	no assertion criteria provided	clinical testing
Gynecological Pathology Laboratory, Kaohsiung Medical University Chung-Ho Memorial Hospital	RCV002480276	SCV002769683	established risk allele	Endometrioid adenocarcinoma		no assertion criteria provided	clinical testing