Submissions for variant NM_006231.4(POLE):c.6817A>T (p.Thr2273Ser)

gnomAD frequency: 0.00444  dbSNP: rs73481453

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760039	SCV000289485	benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000231258	SCV000489041	benign	Colorectal cancer, susceptibility to, 12	2016-08-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000426951	SCV000518897	likely benign	not specified	2018-01-18	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	RCV000562384	SCV000671243	benign	Hereditary cancer-predisposing syndrome	2015-06-04	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	RCV000426951	SCV000806850	benign	not specified	2016-12-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000426951	SCV000889789	benign	not specified	2017-06-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000426951	SCV000920074	benign	not specified	2018-08-27	criteria provided, single submitter	clinical testing	Variant summary: POLE c.6817A>T (p.Thr2273Ser) results in a conservative amino acid change in 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 0.0015 in 276634 control chromosomes, predominantly at a frequency of 0.016 within the African subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 1126 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 a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.6817A>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000760039	SCV001158157	benign	not provided	2020-03-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000426951	SCV002550015	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000231258	SCV004017064	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000760039	SCV005217298	likely benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000562384	SCV000788193	likely benign	Hereditary cancer-predisposing syndrome	2017-09-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358455	SCV001554192	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Thr2273Ser variant was not identified in the literature. The variant was identified in dbSNP (ID: rs73481453) as “With other allele” and ClinVar (classified as benign by Invitae, Ambry Genetics and 4 other submitters; and as likely benign by GeneDx and 1 other submitter). The variant was identified in control databases in 424 (5 homozygous) of 276634 chromosomes at a frequency of 0.002, 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 385 (5 homozygous) of 23998 chromosomes (freq: 0.02), Other in 5 of 6450 chromosomes (freq: 0.0008), Latino in 28 of 34420 chromosomes (freq: 0.0008), European Non-Finnish in 5 of 126184 chromosomes (freq: 0.00004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, East Asian, or European Finnish populations. The p.Thr2273Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Ser impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000426951	SCV003839899	benign	not specified	2022-07-27	no assertion criteria provided	clinical testing