Submissions for variant NM_006231.4(POLE):c.1336C>T (p.Arg446Trp)

gnomAD frequency: 0.00004  dbSNP: rs200403177

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484768	SCV000570827	uncertain significance	not provided	2016-06-30	criteria provided, single submitter	clinical testing	This variant is denoted POLE c.1336C>T at the cDNA level, p.Arg446Trp (R446W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in at least one endometrial tumor (Billingsley 2015). POLE Arg446Trp was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. POLE Arg446Trp occurs at a position that is conserved in mammals and is located within the exonuclease domain (Preston 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether POLE Arg446Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000484768	SCV000823205	uncertain significance	not provided	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 446 of the POLE protein (p.Arg446Trp). This variant is present in population databases (rs200403177, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29120461). ClinVar contains an entry for this variant (Variation ID: 421572). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. 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.
Sema4, Sema4	RCV002258931	SCV002536745	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	curation
Ambry Genetics	RCV002258931	SCV002694499	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-13	criteria provided, single submitter	clinical testing	The p.R446W variant (also known as c.1336C>T), located in coding exon 13 of the POLE gene, results from a C to T substitution at nucleotide position 1336. The arginine at codon 446 is replaced by tryptophan, an amino acid with dissimilar properties. In one family, this alteration was detected in an individual with colorectal cancer diagnosed at age 45, two of this individual's siblings with lower limb cancers, and another sibling with breast cancer. Two additional unaffected siblings and an unaffected paternal aunt from this family tested negative for this alteration (Buchanan DD et al. Genet Med, 2018 08;20:890-895). In another study, this variant was not detected in 165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV000694747	SCV004203538	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-09-05	criteria provided, single submitter	clinical testing