Submissions for variant NM_002691.4(POLD1):c.2360C>T (p.Pro787Leu)

gnomAD frequency: 0.00004  dbSNP: rs199783227

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235244	SCV000294014	uncertain significance	not provided	2018-01-15	criteria provided, single submitter	clinical testing	This variant is denoted POLD1 c.2360C>T at the cDNA level, p.Pro787Leu (P787L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a colorectal cancer and other cancer(s) of unspecified type (Palles 2013, Campbell 2017). POLD1 Pro787Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Polymerase domain (Preston 2010). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether POLD1 Pro787Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705985	SCV000835012	uncertain significance	Colorectal cancer, susceptibility to, 10	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 787 of the POLD1 protein (p.Pro787Leu). This variant is present in population databases (rs199783227, gnomAD 0.02%). 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: 246453). 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.
Fulgent Genetics, Fulgent Genetics	RCV005016648	SCV005650309	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome; Immunodeficiency 120	2024-01-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532987	SCV004725115	uncertain significance	POLD1-related disorder	2023-11-05	no assertion criteria provided	clinical testing	The POLD1 c.2360C>T variant is predicted to result in the amino acid substitution p.Pro787Leu. To our knowledge, this variant has not been reported as a germline variant in the literature. This variant is reported in 0.029% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50917108-C-T) and is interpreted as uncertain significance in ClinVar (www.ncbi.nlm.nih.gov/clinvar/variation/246453). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.