Submissions for variant NM_006231.4(POLE):c.6494G>A (p.Arg2165His)

gnomAD frequency: 0.00550  dbSNP: rs5745068

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000759315	SCV000261708	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000204118	SCV000488502	likely benign	Colorectal cancer, susceptibility to, 12	2016-06-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000438859	SCV000518489	benign	not specified	2017-05-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000492600	SCV000581376	likely benign	Hereditary cancer-predisposing syndrome	2015-05-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000438859	SCV000806838	benign	not specified	2017-07-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000438859	SCV000888567	benign	not specified	2017-08-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000438859	SCV000920072	benign	not specified	2018-01-29	criteria provided, single submitter	clinical testing	Variant summary: POLE c.6494G>A (p.Arg2165His) 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 0.0057 in 269142 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 402 fold above 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. The variant c.6494G>A has been reported in the literature in individuals affected with Colorectal Cancer. These report(s) do not provide unequivocal conclusions about the association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with all laboratories classifying the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000759315	SCV001502158	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	POLE: BS1, BS2
Genetic Services Laboratory, University of Chicago	RCV000438859	SCV002065115	likely benign	not specified	2021-08-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000492600	SCV002536916	benign	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000438859	SCV002550033	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000204118	SCV004016683	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759315	SCV004564078	benign	not provided	2023-10-05	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000492600	SCV000788191	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000438859	SCV001551484	benign	not specified		no assertion criteria provided	clinical testing	The POLE p.Arg2165His variant was identified in 6 of 600 proband chromosomes (frequency: 0.01) from individuals or families with endometrial carcinoma and breast cancer (Wong 2016, Maxwell 2016). The variant was also identified in the following databases: dbSNP (ID: rs5745068) as "With other allele", ClinVar (4x likely benign, 1x benign), and Clinvitae. The variant was not identified in Cosmic or the MutDB database. The variant was identified in control databases in 1538 of 269142 chromosomes (10 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 191 of 23136 chromosomes (freq: 0.008), Other in 48 of 6318 chromosomes (freq: 0.008), Latino in 93 of 33642 chromosomes (freq: 0.003), European in 474 of 122460 chromosomes (freq: 0.004), Ashkenazi Jewish in 117 of 9978 chromosomes (freq: 0.01), East Asian in 180 of 18418 chromosomes (freq: 0.01), Finnish in 8 of 25212 chromosomes (freq: 0.0003), and South Asian in 427 of 29978 chromosomes (freq: 0.01). The p.Arg2165 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000438859	SCV001808704	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000438859	SCV001917021	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000438859	SCV001953348	benign	not specified		no assertion criteria provided	clinical testing