Submissions for variant NM_006231.4(POLE):c.941C>G (p.Ser314Ter)

gnomAD frequency: 0.00001  dbSNP: rs869312803

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000409118	SCV000266226	likely benign	Colorectal cancer, susceptibility to, 12	2017-10-30	criteria provided, single submitter	clinical testing	A large study of hypermutated tumors describes specific missense driver mutations in POLE (Campbell 2017). Variants in POLE that increase cancer risk cause increased mutations in replicating DNA by specifically altering the exonuclease, or proofreading, activity while maintaining the polymerase, or DNA synthesis, activity of this enzyme Truncating variants that eliminate all polymerase activity are not predicted to produce a similar hypermutation phenotype. Consistently, there are no reported observations of truncating variants in the POLE gene, such as p.S314*, causing hypermutation in tumors with increased cancer risk.
GeneDx	RCV000766971	SCV000293502	likely pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with breast cancer (Shirts et al., 2016); This variant is associated with the following publications: (PMID: 27244218, 29056344, 26845104)
Counsyl	RCV000409118	SCV000489237	uncertain significance	Colorectal cancer, susceptibility to, 12	2016-09-07	criteria provided, single submitter	clinical testing
Invitae	RCV000766971	SCV000544034	pathogenic	not provided	2023-10-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser314*) in the POLE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224590). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000210076	SCV000671331	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-12	criteria provided, single submitter	clinical testing	The p.S314* variant (also known as c.941C>G), located in coding exon 10 of the POLE gene, results from a C to G substitution at nucleotide position 941. This changes the amino acid from a serine to a stop codon within coding exon 10. This alteration has been reported as a variant of uncertain significance in a patient with breast cancer from a cohort of 1,462 sequential patients referred for testing by multi-gene panels (Shirts BH et al. Genet. Med. 2016 10;18:974-81). This region is highly conserved in available vertebrate species. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay; however, loss of function of POLE has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000235565	SCV000731468	uncertain significance	not specified	2017-04-21	criteria provided, single submitter	clinical testing	The p.Ser314X variant in POLE has been reported in 1 individual with breast canc er (Shirts 2015), has also been reported in ClinVar (Variation ID 224590) and wa s absent from large population studies. This nonsense variant leads to a prematu re termination codon at position 314, which is predicted to lead to a truncated or absent protein. Although this variant is expected to severely impact the prot ein, the POLE gene has not yet been widely studied in patients (to date, virtual ly all variants reported in patients with colorectal cancer represent missense c hanges). In summary, the clinical significance of the p.Ser314X variant is uncer tain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766971	SCV001134768	uncertain significance	not provided	2018-09-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417758	SCV004108834	uncertain significance	POLE-related condition	2022-12-16	criteria provided, single submitter	clinical testing	The POLE c.941C>G variant is predicted to result in premature protein termination (p.Ser314*). This variant has been reported as a variant of uncertain significance in an individual with breast cancer (Table S1 - Shirts et al. 2016. PubMed ID: 26845104). This variant is not present in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Missense variants that disrupt the proofreading, but not the polymerase, activity of the POLE protein have been predominantly implicated in colorectal adenomas and carcinomas (Palles et al. 2013, PubMed ID: 23263490; Briggs & Tomlinson 2013. PubMed ID: 23447401). The effect of truncating variants that would significantly disrupt or abolish POLE protein function is unclear (Lorca et al. 2019. PubMed ID: 31285513; ClinVar). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.