Submissions for variant NM_006231.4(POLE):c.4184A>G (p.Tyr1395Cys)

gnomAD frequency: 0.00240  dbSNP: rs5744933

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256131	SCV000322483	likely benign	not specified	2018-03-13	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000256131	SCV000602042	uncertain significance	not specified	2017-01-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000256131	SCV000806774	benign	not specified	2017-10-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000256131	SCV000918086	benign	not specified	2018-07-13	criteria provided, single submitter	clinical testing	Variant summary: POLE c.4184A>G (p.Tyr1395Cys) 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 0.00074 in 277082 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 52-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.4184A>G in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x likely benign/benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226045	SCV001729066	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000256131	SCV002066990	likely benign	not specified	2021-11-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257581	SCV002536838	benign	Hereditary cancer-predisposing syndrome	2020-10-31	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000226045	SCV003799232	likely benign	not provided	2022-05-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000256131	SCV004243489	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356856	SCV001552128	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Tyr1395Cys variant was not identified in the literature. The variant was identified in dbSNP (ID: rs5744933) as "With other allele" and in ClinVar (classified as benign by Invitae and Prevention Genetics; as likely benign by GeneDx; and as uncertain significance by one submitter). The variant was identified in control databases in 206 of 277082 chromosomes (1 homozygous) at a frequency of 0.0007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 189 of 24032 chromosomes (1 homozygous; freq: 0.008, increasing the likelihood this could be a low frequency benign variant), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 15 of 34408 chromosomes (freq: 0.0004), European in 1 of 126596 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Tyr1395 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.