Submissions for variant NM_006231.4(POLE):c.2090C>G (p.Pro697Arg)

dbSNP: rs36120395

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657066	SCV000289287	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000657066	SCV000293173	likely benign	not provided	2021-03-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28717660, 28873162, 27244218, 31780696)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000235798	SCV000540090	uncertain significance	not specified	2016-10-13	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant not in HGMD, conflicting classifications in ClinVar. MaxMAF = 0.13%. AA not conserved but Arg not in any species.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235798	SCV000601995	uncertain significance	not specified	2017-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565117	SCV000671278	benign	Hereditary cancer-predisposing syndrome	2024-02-27	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.
PreventionGenetics, part of Exact Sciences	RCV000657066	SCV000806739	likely benign	not provided	2017-05-04	criteria provided, single submitter	clinical testing
Mendelics	RCV003492007	SCV000838701	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235798	SCV001370689	likely benign	not specified	2020-05-26	criteria provided, single submitter	clinical testing	Variant summary: POLE c.2090C>G (p.Pro697Arg) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain (IPR006134) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00091 in 249370 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 64 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 benign. c.2090C>G has been reported in the literature in sequencing studies of individuals affected with colorectal cancer, and breast cancer (example, Bonache_2018, Kothari_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory ( BRCA2 c.4271delC , p.Ser1424LeufsX24), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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 (likely benign, n=2; VUS, n=7). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657066	SCV002048173	likely benign	not provided	2020-10-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000235798	SCV002071550	uncertain significance	not specified	2021-09-22	criteria provided, single submitter	clinical testing	DNA sequence analysis of the POLE gene demonstrated a sequence change, c.2090C>G, in exon 19 that results in an amino acid change, p.Pro697Arg. This sequence change has been described in the gnomAD database with a frequency of 0.15% in the European sub-population (dbSNP rs36120395). The p.Pro697Arg change has been identified in two BRCA1/BRCA2-negative individuals with a personal history of breast cancer (PMID: 31780696). The p.Pro697Arg change affects a highly conserved amino acid residue located in a domain of the POLE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro697Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro697Arg change remains unknown at this time.
Sema4, Sema4	RCV000565117	SCV002536774	likely benign	Hereditary cancer-predisposing syndrome	2021-07-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235798	SCV002550162	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000657066	SCV003917260	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	POLE: BP4
Mayo Clinic Laboratories, Mayo Clinic	RCV000657066	SCV004226393	uncertain significance	not provided	2023-01-12	criteria provided, single submitter	clinical testing	BP4
True Health Diagnostics	RCV000565117	SCV000788165	uncertain significance	Hereditary cancer-predisposing syndrome	2017-11-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000657066	SCV001553477	uncertain significance	not provided		no assertion criteria provided	clinical testing	The POLE p.Pro697Arg variant was identified in 1 of 72 proband chromosomes (frequency: 0.01) from individuals or families with personal or familial history of cancer (Cabanillas 2017). The variant was also identified in dbSNP (ID: rs36120395) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and PreventionGenetics; as uncertain significance by GeneDx, Ambry Genetics and four other submitters). The variant was identified in control databases in 257 of 275186 chromosomes (1 homozygous) at a frequency of 0.0009 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 10 of 23976 chromosomes (freq: 0.0004), Other in 8 of 6408 chromosomes (freq: 0.001), Latino in 39 of 34078 chromosomes (freq: 0.001), European in 190 of 125844 chromosomes (freq: 0.002), Finnish in 8 of 25670 chromosomes (freq: 0.0003), and South Asian in 2 of 30444 chromosomes (freq: 0.00007), while the variant was not observed in the Ashkenazi Jewish, and East Asian, populations. The p.Pro697 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.
Clinical Genetics, Academic Medical Center	RCV000657066	SCV001917041	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000657066	SCV001926416	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000657066	SCV001970029	likely benign	not provided		no assertion criteria provided	clinical testing