Submissions for variant NM_006231.4(POLE):c.844C>T (p.Pro282Ser)

gnomAD frequency: 0.00005  dbSNP: rs138207610

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210101	SCV000266224	uncertain significance	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679671	SCV000289496	uncertain significance	not provided	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 282 of the POLE protein (p.Pro282Ser). This variant is present in population databases (rs138207610, gnomAD 0.01%). This missense change has been observed in individual(s) with cutaneous malignant melanoma and Merkel cell carcinoma, and familial colorectal cancer (PMID: 26251183, 28195393, 29120461). ClinVar contains an entry for this variant (Variation ID: 224588). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLE protein function with a positive predictive value of 80%. 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.
Counsyl	RCV000229770	SCV000489555	uncertain significance	Colorectal cancer, susceptibility to, 12	2016-10-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210101	SCV000671436	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-12	criteria provided, single submitter	clinical testing	The p.P282S variant (also known as c.844C>T), located in coding exon 9 of the POLE gene, results from a C to T substitution at nucleotide position 844. The proline at codon 282 is replaced by serine, an amino acid with similar properties. This alteration has been reported in an individual with familial colorectal cancer who previously tested negative for Lynch syndrome mutations (Hansen MF et al. Clin Genet, 2017 Oct;92:405-414). This alteration was detected in the 669 population-based probands with colorectal cancer from the Australasian Colorectal Cancer Family Registry (Buchanan DD et al. Genet Med, 2018 08;20:890-895). It was also observed in an individual diagnosed with breast cancer (Shirts BH et al. Genet Med, 2016 10;18:974-81). In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 3/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This alteration was also identified in 3/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	RCV000607043	SCV000731304	uncertain significance	not specified	2016-11-22	criteria provided, single submitter	clinical testing	The p.Pro282Ser variant in POLE has been reported in 1 individual with cutaneous malignant melanoma and 1 individual with breast cancer (Aoude 2015, Shirts 2016 ). It has also been identified in 10/66546 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs138207610) . Computational prediction tools and conservation analysis suggest that the vari ant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro282Se r variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV000679671	SCV000806856	uncertain significance	not provided	2017-12-08	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000735962	SCV000864151	uncertain significance	Colorectal cancer	2015-09-01	criteria provided, single submitter	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 37 year old female diagnosed with colon cancer at age 30. No family history of colorectal cancer or colon polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679671	SCV000889794	uncertain significance	not provided	2021-03-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000607043	SCV000920068	likely benign	not specified	2019-11-05	criteria provided, single submitter	clinical testing	Variant summary: POLE c.844C>T (p.Pro282Ser) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 282822 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9-fold the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.844C>T has been reported in the literature in individuals affected with colorectal cancer, breast cancer, and cutaneous melanoma (Hansen_2017, Shirts_2015, Aoude_2015). These reports do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679671	SCV001473928	uncertain significance	not provided	2020-02-02	criteria provided, single submitter	clinical testing	The POLE c.844C>T; p.Pro282Ser variant (rs138207610) is reported in the literature in an individual with cutaneous melanoma (Aoude 2015), an individual with familial colorectal cancer (Hansen 2017), and in an individual with a family history of breast cancer (Shirts 2016). This variant is also reported in CilnVar (Variation ID: 224588). It is found in the general population with an overall allele frequency of 0.006% (17/282822 alleles) in the Genome Aggregation Database. The proline at codon 282 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, this variant is located within the exonuclease domain (Palles 2013), and gene-disease association has been established for variants within this domain (Seifert 2019). However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Aoude LG et al. POLE mutations in families predisposed to cutaneous melanoma. Fam Cancer. 2015 Dec;14(4):621-8. Hansen MF et al. Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome. Clin Genet. 2017 Oct;92(4):405-414. Palles C et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516. Shirts BH et al. Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med. 2016 Oct;18(10):974-81.
GeneDx	RCV000679671	SCV001767007	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal and/or family history of melanoma, breast cancer, or colorectal cancer (PMID: 26251183, 26845104, 29120461, 28195393, 34326862); This variant is associated with the following publications: (PMID: 30267214, 26251183, 26845104, 28195393, 30917185, 29120461, 29641532, 20951805, 34326862)
Sema4, Sema4	RCV000210101	SCV002536947	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-05	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000229770	SCV004018523	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-04-19	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000229770	SCV004203532	uncertain significance	Colorectal cancer, susceptibility to, 12	2024-03-24	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535476	SCV001749406	not provided	Familial colorectal cancer; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-20-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.