Submissions for variant NM_002691.4(POLD1):c.2954G>A (p.Arg985Gln)

dbSNP: rs749159160

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000458259	SCV000547549	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 985 of the POLD1 protein (p.Arg985Gln). This variant is present in population databases (rs749159160, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. 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: 408002). 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.
GeneDx	RCV001358205	SCV002558123	uncertain significance	not provided	2022-07-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31034466)
Ambry Genetics	RCV002436419	SCV002750171	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-11	criteria provided, single submitter	clinical testing	The p.R985Q variant (also known as c.2954G>A) is located in coding exon 23 of the POLD1 gene. The arginine at codon 985 is replaced by glutamine, an amino acid with highly similar 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358205	SCV001553878	uncertain significance	not provided		no assertion criteria provided	clinical testing	The POLD1 p.R985Q variant was not identified in the literature nor was it identified in COSMIC. The variant was identified in dbSNP (ID: rs749159160) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 13 of 163266 chromosomes at a frequency of 0.00007962, and was observed at the highest frequency in the Latino population in 11 of 26294 chromosomes (freq: 0.0004183) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.R985 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome, dbscSNV Ada, RF) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.