ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.583C>T (p.Arg195Ter)

gnomAD frequency: 0.00001  dbSNP: rs377690809
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000231988 SCV000287639 likely benign Colorectal cancer, susceptibility to, 10 2025-02-02 criteria provided, single submitter clinical testing
Counsyl RCV000231988 SCV000489130 uncertain significance Colorectal cancer, susceptibility to, 10 2016-08-23 criteria provided, single submitter clinical testing
GeneDx RCV000479381 SCV000571819 uncertain significance not provided 2023-04-19 criteria provided, single submitter clinical testing Segregates with disease in affected individuals in the literature, but also identified in several control subjects without history of colorectal cancer or polyps (Rosner et al., 2018); Some missense variants in POLD1 have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP); however, there are no data at this time to support that loss-of-function variants confer the same cancer risks; This variant is associated with the following publications: (PMID: 25986922, 33809179, 30086056, 23263490)
Ambry Genetics RCV000576035 SCV000671025 uncertain significance Hereditary cancer-predisposing syndrome 2024-09-06 criteria provided, single submitter clinical testing The p.R195* variant (also known as c.583C>T), located in coding exon 4 of the POLD1 gene, results from a C to T substitution at nucleotide position 583. This changes the amino acid from an arginine to a stop codon within coding exon 4. In one study, this alteration was detected in 1/132 Jewish patients with colorectal adenomas and/or early-onset, mismatch repair proficient colorectal cancer as well as in 5/5685 control subjects without colorectal adenomas or cancer (Rosner G et al. Dis. Colon Rectum, 2018 09;61:1073-1079). This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of POLD1 has not been established as a mechanism of disease. Based on the available evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen RCV000479381 SCV001502262 uncertain significance not provided 2022-09-01 criteria provided, single submitter clinical testing POLD1: PP3
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000479381 SCV002010548 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000576035 SCV002534691 likely benign Hereditary cancer-predisposing syndrome 2021-01-18 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002465586 SCV002761046 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005016638 SCV005650284 uncertain significance Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome; Immunodeficiency 120 2024-01-04 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004737363 SCV005346491 uncertain significance POLD1-related disorder 2024-05-12 no assertion criteria provided clinical testing The POLD1 c.583C>T variant is predicted to result in premature protein termination (p.Arg195*). This variant has been reported in the heterozygous state in an individual with early-onset MMR-proficient colorectal cancer (Table 4 in Rosner et al. 2018. PubMed ID: 30086056). However, the established mechanism for POLD1-related malignancy involves missense mutations that disrupt the protein proof-reading domain (Palles et al. 2013. PubMed ID: 23263490) and there is currently no evidence to suggest that truncating variants cause disease. In the gnomAD public population database this variant has been reported in up to 0.16 % of alleles in a subpopulation and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/239357/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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