Submissions for variant NM_006231.4(POLE):c.4523G>A (p.Arg1508His)

gnomAD frequency: 0.00170  dbSNP: rs142508245

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000590106	SCV000289389	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000590106	SCV000293174	likely benign	not provided	2020-12-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25801821, 29458332, 30171174, 29320758)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000236616	SCV000540088	likely benign	not specified	2016-10-31	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: This variant is not present in HGMD and has not been reported in affected individuals. It is classified in ClinVar with 1 star as Likely Benign by Invitae and VUS by GeneDx. It is present in ExAC with a frequency of 0.27% (high frequency for disease incidence and gene contribution). 2 mammals have a Histidine at this position.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236616	SCV000602048	uncertain significance	not specified	2017-03-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566255	SCV000671258	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590106	SCV000698668	benign	not provided	2017-06-23	criteria provided, single submitter	clinical testing	Variant summary: The POLE c.4523G>A (p.Arg1508His) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 128/120124 control chromosomes at a frequency of 0.0010656, which is approximately 75 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. An internal LCA sample reports the variant to co-occur with two pathogenic MUTYH variants, c.1187G>A and c.536A>G. Taken together, this variant is classified as benign.
Mendelics	RCV000988934	SCV001138867	benign	Colorectal cancer, susceptibility to, 12	2023-08-22	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000590106	SCV002009575	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001788091	SCV002030281	uncertain significance	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2021-04-29	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory, University of Chicago	RCV000236616	SCV002066968	likely benign	not specified	2021-09-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000566255	SCV002536854	benign	Hereditary cancer-predisposing syndrome	2020-11-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236616	SCV002550090	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590106	SCV004136746	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	POLE: BP4, BS1
Mayo Clinic Laboratories, Mayo Clinic	RCV000590106	SCV004226390	uncertain significance	not provided	2022-03-16	criteria provided, single submitter	clinical testing	BS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590106	SCV004563332	likely benign	not provided	2023-08-25	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000566255	SCV000805301	uncertain significance	Hereditary cancer-predisposing syndrome	2018-03-15	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529407	SCV000806784	likely benign	POLE-related disorder	2022-03-17	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	RCV001357004	SCV001552325	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Arg1508His variant was not identified in the literature. The variant was identified in dbSNP (ID: rs142508245) as "With other allele ", ClinVar (classified as benign by Integrated Genetics/Laboratory Corporation of America; as likely benign by Invitae, Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine; as uncertain significance by GeneDx, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae, Cosmic (1x stomach), MutDB, or LOVD 3.0 (3x likely benign). The variant was identified in control databases in 309 of 272998 chromosomes at a frequency of 0.001 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 54 of 23804 chromosomes (freq: 0.002), Other in 9 of 6386 chromosomes (freq: 0.001), Latino in 34 of 34334 chromosomes (freq: 0.001), European in 200 of 123186 chromosomes (freq: 0.002), Ashkenazi Jewish in 6 of 10012 chromosomes (freq: 0.001), Finnish in 5 of 25736 chromosomes (freq: 0.0002), and South Asian in 1 of 30718 chromosomes (freq: 0.00003); it was not observed in the East Asian population. The p.Arg1508 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000590106	SCV001809102	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000590106	SCV001906246	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000590106	SCV001918533	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000590106	SCV001964326	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000590106	SCV001978137	likely benign	not provided		no assertion criteria provided	clinical testing