Submissions for variant NM_006231.4(POLE):c.139C>T (p.Arg47Trp)

gnomAD frequency: 0.00082  dbSNP: rs143626223

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679599	SCV000289254	likely benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000679599	SCV000292980	likely benign	not provided	2021-04-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29987844)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236828	SCV000601979	uncertain significance	not specified	2016-11-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574273	SCV000671274	benign	Hereditary cancer-predisposing syndrome	2024-02-22	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	RCV000709281	SCV000838712	likely benign	Familial colorectal cancer	2024-04-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679599	SCV001148916	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	POLE: BP4, BS1
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000679599	SCV002009607	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679599	SCV002506068	uncertain significance	not provided	2022-01-04	criteria provided, single submitter	clinical testing	The POLE c.139C>T; p.Arg47Trp variant (rs143626223) is reported in the literature in one individual with suspected Lynch syndrome, but without clear disease association (Kayser 2018). This variant is also reported in ClinVar (Variation ID: 240391) and is found in the general population with an overall allele frequency of 0.079% (223/282858 alleles) in the Genome Aggregation Database. The arginine at codon 47 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.132). 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). However, given the lack of clinical and functional data, the significance of the p.Arg47Trp variant is uncertain at this time. References: Kayser et al. Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes. Int J Cancer. 2018 Dec 1;143(11):2800-2813. PMID 29987844. 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.
Sema4, Sema4	RCV000574273	SCV002536751	likely benign	Hereditary cancer-predisposing syndrome	2021-01-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236828	SCV002550225	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236828	SCV002572138	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: POLE c.139C>T (p.Arg47Trp) results in a non-conservative amino acid change in 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 0.00079 in 251472 control chromosomes (gnomAD), predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. c.139C>T has been reported in the literature in individuals affected hereditary cancers (Kayser_2018, Mur_2020, Guindalini_2022) and inflammatory bowel disease (Biscaglia_2022). These reports do not provide unequivocal conclusions about association of the variant with Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, Genital Anomalies, And Immunodeficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34347074, 35264596, 29987844, 32792570). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS=8, likely benign=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001083219	SCV002584735	uncertain significance	Colorectal cancer, susceptibility to, 12	2024-10-19	criteria provided, single submitter	clinical testing	The POLE c.139C>T (p.Arg47Trp) missense change has a maximum subpopulation frequency of 0.12% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is not located in the exonuclease domain. The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer, inflammatory bowel disease, ovarian cancer, and non-cancer control individuals (PMID: 29641532, 29987844, 31240875, 32546565, 34347074). This variant was found to co-segregate in one family with glioblastoma and colorectal cancer (PMID: 37990341). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001083219	SCV005373806	likely benign	Colorectal cancer, susceptibility to, 12	2024-09-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529401	SCV000806720	likely benign	POLE-related disorder	2020-06-22	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).
True Health Diagnostics	RCV000574273	SCV000886707	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-13	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356982	SCV001552291	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Arg47Trp variant was not identified in the literature nor was it identified in the MutDB, database. The variant was identified in dbSNP (ID: rs143626223) as "With other allele ", ClinVar (classified as likely benign by Invitae, GeneDx; as uncertain significance by Ambry Genetics and two clinical laboratories), and in Cosmic (1x in Genital tract) database. The variant was identified in control databases in 219 of 277204 chromosomes at a frequency of 0.0008 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 4 of 24032 chromosomes (freq: 0.0002), Other in 7 of 6464 chromosomes (freq: 0.001), Latino in 4 of 34420 chromosomes (freq: 0.0001), European in 161 of 126700 chromosomes (freq: 0.001), Finnish in 30 of 25784 chromosomes (freq: 0.001), and South Asian in 13 of 30782 chromosomes (freq: 0.0004), while the variant was not observed in the Ashkenazi Jewish, and East Asian, populations. The p.Arg47 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.