Submissions for variant NM_006231.4(POLE):c.779G>A (p.Arg260Gln)

gnomAD frequency: 0.00312  dbSNP: rs5744752

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760041	SCV000261346	benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000760041	SCV000521986	likely benign	not provided	2022-03-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26251183, 15766587)
Ambry Genetics	RCV000567672	SCV000671227	likely benign	Hereditary cancer-predisposing syndrome	2015-07-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000433874	SCV000806855	benign	not specified	2017-09-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000433874	SCV000889792	benign	not specified	2018-05-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000567672	SCV002536941	benign	Hereditary cancer-predisposing syndrome	2020-02-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000433874	SCV002760999	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001080216	SCV004016706	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000760041	SCV004136760	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	POLE: BP4, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000760041	SCV005219274	likely benign	not provided		criteria provided, single submitter	not provided
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000760041	SCV005877728	likely benign	not provided	2024-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000433874	SCV005887591	likely benign	not specified	2025-01-30	criteria provided, single submitter	clinical testing	Variant summary: POLE c.779G>A (p.Arg260Gln) results in a conservative amino acid change located in the Ribonuclease H-like domain 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 0.00084 in 251484 control chromosomes, predominantly at a frequency of 0.01 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Facial Dysmorphism, Immunodeficiency, Livedo, And Short Stature phenotype (0.0011). ClinVar contains an entry for this variant (Variation ID: 220642). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000760041	SCV001550984	likely benign	not provided		no assertion criteria provided	clinical testing	The POLE p.Arg260Gln variant was not identified in the literature nor was it identified in the databases. The variant was identified in dbSNP (ID: rs5744752) as "With Likely benign allele", in ClinVar (classified as benign by Invitae, Prevention Genetics, Quest Diagnostics; as likely benign by GeneDx and Ambry Genetics). The variant was identified in control databases in 289 of 277244 chromosomes (4 homozygous) at a frequency of 0.001 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 237 of 24036 chromosomes (freq: 0.0099), Other in 3 of 6468 chromosomes (freq: 0.0005), Latino in 28 of 34420 chromosomes (freq: 0.0008), European Non-Finnish in 18 of 126726 chromosomes (freq: 0.0001), East Asian in 2 of 18868 chromosomes (freq: 0.0001), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish or European Finnish populations. The p.Arg260 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 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	RCV000760041	SCV001808516	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000760041	SCV001919272	likely benign	not provided		no assertion criteria provided	clinical testing