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

dbSNP: rs1057519943

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766182	SCV000653485	uncertain significance	not provided	2017-01-12	criteria provided, single submitter	clinical testing	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. 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). 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 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.
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV005251126	SCV005901740	likely pathogenic	Hereditary cancer-predisposing syndrome	2025-02-05	criteria provided, single submitter	clinical testing	PM1, PM2_Supporting, PP4_Strong, PS3_Supporting c.857C>G is located in exon 9 of the POLE gene, is predicted to result in the substitution of proline by arginine at codon 286, p.(Pro286Arg). This variant is located at exonuclease domain in a mutation hotspot (PM1). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.837) suggests a deleterious effect on protein function. Whole Exome Sequencing in multiple tumours (MSI and MSS) from TGCA/COSMIC database carrying this variant showed that all of them are hyper or ultramutated and have >50% of combined contribution of signature SBS10 and SBS14 (PMID: 32792570)(PP4_Strong). Functional assays performed in cell lines showed a reduced exonuclease repair function (PMID: 25228659) (PS3_Supporting).In addition, this variant has been reported in the ClinVar (1x uncertain significance, 1x risk allele, 1x drug response)) and in the LOVD database (1x pathogenic). Based on currently available information, the variant c.857C>G is classified as a likely pathogenic variant according to POLE/POLD1 Guidelines (PMID 37848928).
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