Submissions for variant NM_002691.4(POLD1):c.2560G>A (p.Asp854Asn)

dbSNP: rs373650022

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229984	SCV000287581	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 854 of the POLD1 protein (p.Asp854Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 239299). 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 not expected to disrupt POLD1 protein function with a negative 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.
GeneDx	RCV000480703	SCV000568476	uncertain significance	not provided	2023-09-13	criteria provided, single submitter	clinical testing	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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480703	SCV001134643	uncertain significance	not provided	2020-04-20	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000480703	SCV002010602	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002518332	SCV003744936	uncertain significance	Inborn genetic diseases	2022-05-25	criteria provided, single submitter	clinical testing	The c.2560G>A (p.D854N) alteration is located in exon 20 (coding exon 19) of the POLD1 gene. This alteration results from a G to A substitution at nucleotide position 2560, causing the aspartic acid (D) at amino acid position 854 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003417815	SCV004118166	uncertain significance	POLD1-related condition	2023-05-26	criteria provided, single submitter	clinical testing	The POLD1 c.2560G>A variant is predicted to result in the amino acid substitution p.Asp854Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50918243-G-A) and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/239299/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.