Submissions for variant NM_006231.4(POLE):c.4057A>G (p.Ser1353Gly)

gnomAD frequency: 0.00063  dbSNP: rs141619382

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679629	SCV000289364	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000679629	SCV000322188	likely benign	not provided	2021-06-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22885699)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000256048	SCV000602040	likely benign	not specified	2017-03-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571135	SCV000671222	benign	Hereditary cancer-predisposing syndrome	2024-02-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Mendelics	RCV003492008	SCV001138871	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679629	SCV001148887	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	POLE: BP4, BS1:Supporting
Genetic Services Laboratory, University of Chicago	RCV000256048	SCV002067001	uncertain significance	not specified	2019-07-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000571135	SCV002536834	likely benign	Hereditary cancer-predisposing syndrome	2021-01-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000256048	SCV002550104	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679629	SCV003800455	uncertain significance	not provided	2023-02-07	criteria provided, single submitter	clinical testing	The POLE c.4057A>G; p.Ser1353Gly variant (rs141619382) is reported in the literature in individuals affected with cancer, but without clear disease association (Bhai 2021, Garmezy 2022, Mur 2020). This variant is also reported in ClinVar (Variation ID: 240500), and is found in the general population with an overall allele frequency of 0.06% (157/281776 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.168). Additionally, this variant is not located in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bhai P et al. Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. Front Genet. 2021 Jul 13;12:698595. PMID: 34326862. Garmezy B et al. Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers. JCO Precis Oncol. 2022 Feb;6:e2100267. PMID: 35108036. Mur P et al. Role of POLE and POLD1 in familial cancer. Genet Med. 2020 Dec;22(12):2089-2100. PMID: 32792570. 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. PMID: 23263490. 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. PMID: 30523343.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000256048	SCV004021043	likely benign	not specified	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: POLE c.4057A>G (p.Ser1353Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 250366 control chromosomes, predominantly at a frequency of 0.0008 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 56-fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism. The variant, c.4057A>G, has been reported in the literature in individuals affected with polyposis and other tumor phenotypes (e.g. Mur_2020, Garmezy_2022), however without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is located outside of the exonuclease domain, and while missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLE protein have been known to be associated with an increased risk for colonic adenomatous polyps and colon cancer, however, missense variants outside the exonuclease domain, are unlikely to be associated with polyposis or colon cancer (see e.g. PMID: 23263490, 23447401). The following publications have been ascertained in the context of this evaluation (PMID: 32792570, 35108036). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.
True Health Diagnostics	RCV000571135	SCV000805300	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-05	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529405	SCV000806771	likely benign	POLE-related disorder	2023-02-16	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356346	SCV001551490	uncertain significance	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLE p.Ser1353Gly variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from an individual with advanced cancer (Mandelker 2017). The variant was identified in dbSNP (rs141619382) as “with other allele” and ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, PreventionGenetics and 1 other submitter and likely benign by Invitae and Quest Diagnostics). The variant was identified in control databases in 159 of 276,260 chromosomes at a frequency of 0.0006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 5 of 23,992 chromosomes (freq: 0.0002), Other in 4 of 6450 chromosomes (freq: 0.0006), Latino in 6 of 34,396 chromosomes (freq: 0.0002), European in 108 of 126,130 chromosomes (freq: 0.0009), Finnish in 36 of 25,534 chromosomes (freq: 0.001); it was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The p.Ser1353 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000679629	SCV001808260	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000679629	SCV001917788	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000679629	SCV001931850	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679629	SCV001967327	likely benign	not provided		no assertion criteria provided	clinical testing