POLD1 and POLE-related cancer

Growing evidence indicates that mutations in POLD1 and POLE are associated with increased risk for colorectal cancer and polyposis and are autosomal dominantly inherited. 

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Quick Reference
Test Code: 2842 Test Name: POLD1 specific site analysis TAT 7-14 days Gene: 1
Test Code: 2843 Test Name: POLE specific site analysis TAT 7-14 days Gene: 1
Test Code: 8877 Test Name: POLE & POLD1 seq TAT 14-21 days Genes: 2

Ordering Options

Why Is This Important?

  1. Option to modify frequency and initial age of colonoscopy and other screening
  2. Identify at-risk family members

When To Consider Testing

The following initial guidelines for POLE and POLD1 genetic testing have been suggested:1

POLE

  • 20-100 adenomas
  • Family history that meets the Amsterdam I criteria (CRC only)
  • CRC and 5-20 adenomas, both diagnosed before age 50
  • CRC or 5-20 adenomas, and a first-degree relative with CRC before age 50
  • CRC or 5-20 adenomas and 2 or more first-or second-degree relatives with CRC, regardless of age

POLD1

  • 20-100 adenomas
  • Family history that meets the Amsterdam II criteria (only CRC and EC)
  • CRC before age 50 or EC before age 60, and 5-20 adenomas diagnosed before age 50
  • CRC or EC or 5-20 adenomas and a first-degree relative with CRC before age 50, or EC before age 60
  • CRC or EC or 5-20 adenomas and 2 or more first-or second-degree relatives with CRC or EC, regardless of age

Mutation Detection Rate

Ambry’s POLD1 and POLE testing can detect >99.9% of described mutations in both genes, when present (analytic sensitivity).

Test Description

POLD1 coding exons 1-26 and POLE coding exons 1-49 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing. Missense variants located outside of the exonuclease domains (POLD1 codons 311-541 and POLE codons 269-485) are not routinely reported.

 

1. Bellido F, et al. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet Med. 2015. 

2. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.

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