ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.1561C>T (p.Arg521Trp)

gnomAD frequency: 0.00001  dbSNP: rs1341055535
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000539274 SCV000646492 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-26 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 521 of the POLD1 protein (p.Arg521Trp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 469205). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLD1 protein function with a positive 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.
Ambry Genetics RCV001012187 SCV001172610 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-26 criteria provided, single submitter clinical testing The p.R521W variant (also known as c.1561C>T), located in coding exon 12 of the POLD1 gene, results from a C to T substitution at nucleotide position 1561. The arginine at codon 521 is replaced by tryptophan, an amino acid with dissimilar properties. 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.
Sema4, Sema4 RCV001012187 SCV002534593 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-05 criteria provided, single submitter curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV003114670 SCV003800139 uncertain significance not provided 2022-06-24 criteria provided, single submitter clinical testing The POLD1 c.1561C>T; p.Arg521Trp variant (rs1341055535), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 469205). This variant is found in the general population with an overall allele frequency of 0.002% (5/281942 alleles) in the Genome Aggregation Database. The arginine at codon 521 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.471). This variant is located in the exonuclease domain (Palles 2013), and gene-disease association has been established for variants within the exonuclease domain (Seifert 2019). A different variant at this codon, p.Arg521Gln, is reported in a family with colorectal cancer, and in a cohort of individuals with lipodystrophy (Dron 2020, Mur 2020). Due to limited information, the clinical significance of the p.Arg521Trp variant is uncertain at this time. References: Dron JS et al. Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. BMC Med Genomics. 2020 Feb 10;13(1):23. PMID: 32041611. Mur P et al. Role of POLE and POLD1 in familial cancer. Genet Med. 2020 Dec;22(12):2089-2100. PMID: 32792570. Palles C et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. PMID: 23263490. Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516. PMID: 30523343.
Baylor Genetics RCV000539274 SCV004203473 uncertain significance Colorectal cancer, susceptibility to, 10 2023-08-31 criteria provided, single submitter clinical testing

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