Evidence map›Paper›PMID 41212251›Full record

ArticleFamilial cancer2025

The germline POLD1 c.1420 C > A (p.Leu474Ile) variant segregates with endometrial cancer, colorectal cancer and colonic polyps demonstrating hypermutation and defective POLD1 mutational signatures.

Daniel D Buchanan, Peter Georgeson, Romy Walker, Jihoon E Joo, Mark Clendenning, Julia Como, Ryan O'Keeffe, Alysha Prisc, Yen Lin Chu, Mark A Jenkins and 7 more

Abstract read
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In one paragraph

Article in Familial cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Comprehensive analysis ofJournal of thoracic disease · 2026
    Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Daniel D BuchananColorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Peter GeorgesonColorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Romy WalkerColorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Jihoon E JooColorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Mark ClendenningColorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Julia ComoColorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Ryan O'KeeffeColorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Alysha PriscColorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Yen Lin ChuColorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Mark A JenkinsCollaborative Centre for Genomic Cancer Medicine, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.
Christophe RostyColorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Ingrid M WinshipGenomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Melbourne, VIC, 3000, Australia.
Finlay A MacraeGenomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Melbourne, VIC, 3000, Australia.
Emilia IpCancer Genetics, Liverpool Hospital, Sydney, NSW, 2170, Australia.
Rebecca HarrisFaculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia.
Annabel GoodwinFaculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia.
Khalid MahmoodColorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia. khalid.mahmood@unimelb.edu.au.

Funding

NHMRC GNT1194896NHMRC GNT2026331University of Melbourne Early Career Researcher Grant
6 · The paper itself

Abstract

Germline pathogenic variants within the highly conserved exonuclease domain of the POLD1 gene predisposes to colorectal (CRC) and endometrial (EC) cancers. Tumours with POLD1-deficiency demonstrate unique genomic features including hypermutation and tumour mutational signatures (TMS) SBS10c, SBS10d and SBS20. The classification of variants within POLD1 remains challenging. The utility of incorporating tumour hypermutation status and TMS profiles into POLD1 gene-specific variant classification guidelines developed by ClinGen-InSiGHT remains to be established. We report a family with eight members heterozygous for the germline POLD1 c.1420C > A (p.Leu474Ile) variant. This variant resides within the exonuclease domain, is absent in gnomADv4.1 and is classified as a variant of uncertain clinical significance. Formalin-fixed paraffin embedded tissue and matched blood-derived DNA from person 001 (EC, 1 adenoma, 2 sessile serrated lesions), and two cousins, 009 (EC, 3 adenomas), and 010 (breast cancer, EC, CRC, 4 adenomas, 2 sessile serrated lesions and 1 traditional serrated adenoma) were tested using a custom multigene panel to determine tumour mutational burden (TMB) and TMS. All three ECs demonstrated characteristics of POLD1-deficiency namely hypermutated TMB and predominance of SBS10d. The CRC, 62.8% of the adenomas and 60% of the serrated polyps demonstrated SBS10c as the dominant TMS. EC, CRC, breast and multiple polyps from three family members heterozygous for the germline POLD1 c.1420C > A variant demonstrated hypermutation and SBS10c and SBS10d TMS, genomic features associated with defective POLD1. Somatic TMB and TMS profiling of multiple independent lesions demonstrated utility for identifying POLD1-deficiency suggesting this approach can support variant classification for POLD1.

Indexed as

Colonic PolypsColorectal NeoplasmsDNA Polymerase IIIEndometrial NeoplasmsGerm-Line MutationAdultAgedFemaleGenetic Predisposition to DiseaseHumansMaleMiddle AgedPedigreeDNA Polymerase IIIPOLD1 protein, humanColonic polypsColorectal cancerDNA proofreadingEndometrial cancerExonuclease domainHypermutationMutational signaturesPOLD1POLE

Identifiers

PMID41212251

What OpenQuestion holds

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.