Submissions for variant NM_006231.4(POLE):c.1735C>T (p.Arg579Cys)

gnomAD frequency: 0.00005  dbSNP: rs116260568

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000480031	SCV000544046	uncertain significance	not provided	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 579 of the POLE protein (p.Arg579Cys). This variant is present in population databases (rs116260568, gnomAD 0.007%). This missense change has been observed in individual(s) with POLE-related conditions (PMID: 33821390). ClinVar contains an entry for this variant (Variation ID: 405728). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000480031	SCV000571003	uncertain significance	not provided	2024-07-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with papillary thyroid cancer (PMID: 33821390); This variant is associated with the following publications: (PMID: 29320758, 32169874, 20951805, 33821390)
Mendelics	RCV000463498	SCV001138895	uncertain significance	Colorectal cancer, susceptibility to, 12	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257690	SCV002536765	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-14	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265768	SCV002548404	uncertain significance	not specified	2022-05-12	criteria provided, single submitter	clinical testing	Variant summary: POLE c.1735C>T (p.Arg579Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251482 control chromosomes. c.1735C>T has not to our knowledge been reported in the literature in individuals affected with POLE-related cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
Ambry Genetics	RCV002257690	SCV005481512	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-17	criteria provided, single submitter	clinical testing	The p.R579C variant (also known as c.1735C>T), located in coding exon 16 of the POLE gene, results from a C to T substitution at nucleotide position 1735. The arginine at codon 579 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.