Submissions for variant NM_006231.4(POLE):c.776G>A (p.Arg259His)

gnomAD frequency: 0.00604  dbSNP: rs61732929

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000442441	SCV000262257	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000205994	SCV000489134	likely benign	Colorectal cancer, susceptibility to, 12	2016-08-23	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000442441	SCV000510795	likely benign	not provided	2017-01-06	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
GeneDx	RCV000442441	SCV000518415	likely benign	not provided	2021-06-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24525744, 22573403, 24480973, 29458332)
Genetic Services Laboratory, University of Chicago	RCV000442749	SCV000596497	benign	not specified	2019-04-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000442749	SCV000602099	likely benign	not specified	2017-05-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568305	SCV000671221	likely benign	Hereditary cancer-predisposing syndrome	2015-06-19	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	RCV000442749	SCV000806854	benign	not specified	2017-01-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000205994	SCV001138901	likely benign	Colorectal cancer, susceptibility to, 12	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000442441	SCV001148910	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	POLE: PM5, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000442441	SCV001470815	likely benign	not provided	2023-11-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442749	SCV001478663	benign	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: POLE c.776G>A (p.Arg259His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 251450 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 367 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. To our knowledge, no occurrence of c.776G>A in individuals affected with POLE associated Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000568305	SCV002536940	likely benign	Hereditary cancer-predisposing syndrome	2021-03-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000442749	SCV002550202	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000205994	SCV002761570	likely benign	Colorectal cancer, susceptibility to, 12	2019-11-14	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000442441	SCV005197245	likely benign	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000442441	SCV005219275	likely benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000568305	SCV000788194	likely benign	Hereditary cancer-predisposing syndrome	2017-11-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358195	SCV001553868	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Arg259His variant was identified in 1 of 104 proband chromosomes (frequency: 0.01) from individuals or families with colon cancer (Kane 2014). The variant was identified in dbSNP (ID: rs61732929) as With other allele, ClinVar (1x as benign by Invitae; 5x as likely benign by Counsyl, GeneDx, Ambry Genetics, Children’s Mercy Hospital, and Quest Diagnostics Nichols Institute San Juan Capistrano; and 1x as uncertain significance by University of Chicago), Cosmic, and MutDB. The variant was identified in control databases in 1459 of 277200 chromosomes (8 homozygous) at a frequency of 0.005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was seen in the following populations: African in 55 of 24024 chromosomes (freq: 0.002), Other in 24 of 6466 chromosomes (freq: 0.004), Latino in 81 of 34418 chromosomes (freq: 0.002), European Non-Finnish in 1184 of 126702 chromosomes (freq: 0.01), East Asian in 10 of 18868 chromosomes (freq: 0.0005), Finnish in 89 of 25790 chromosomes (freq: 0.003), and South Asian in 16 of 30780 chromosomes (freq: 0.0005), while the variant was not observed in the Ashkenazi Jewish population. The p.Arg259 residue is conserved in mammals but not in more distantly related organisms; however, 4 of 5 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	RCV000442441	SCV001808703	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000442441	SCV001922942	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000442441	SCV001926813	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000442441	SCV002036124	likely benign	not provided		no assertion criteria provided	clinical testing