Submissions for variant NM_002691.4(POLD1):c.2954G>C (p.Arg985Pro)

gnomAD frequency: 0.00003  dbSNP: rs749159160

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000460737	SCV000547661	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 985 of the POLD1 protein (p.Arg985Pro). This variant is present in population databases (no rsID available, gnomAD no frequency). 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: 408108). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985260	SCV000601928	uncertain significance	not provided	2019-02-26	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000506861	SCV000731486	uncertain significance	not specified	2017-07-18	criteria provided, single submitter	clinical testing	The p.Arg985Pro variant in POLD1 has not been previously reported in the literat ure in individuals with colorectal cancer but has been reported in ClinVar (Vari ation ID 408108). This variant was absent from large population studies. Computa tional prediction tools and conservation analysis suggest that the p.Arg985Pro v ariant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg98 5Pro variant is uncertain.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000985260	SCV001473387	uncertain significance	not provided	2019-09-28	criteria provided, single submitter	clinical testing	The POLD1 c.2954G>C; p.Arg985Pro variant (rs749159160), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 408108). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 985 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time.
GeneDx	RCV000985260	SCV001874835	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000985260	SCV002010407	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002436423	SCV002750051	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-09	criteria provided, single submitter	clinical testing	The p.R985P variant (also known as c.2954G>C) is located in coding exon 23 of the POLD1 gene. The arginine at codon 985 is replaced by proline, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 23. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.