Submissions for variant NM_002691.4(POLD1):c.1786G>A (p.Val596Ile)

gnomAD frequency: 0.00006  dbSNP: rs773180520

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000476043	SCV000547580	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 596 of the POLD1 protein (p.Val596Ile). This variant is present in population databases (no rsID available, 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: 408030). 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	RCV000657102	SCV000569031	uncertain significance	not provided	2017-06-14	criteria provided, single submitter	clinical testing	This variant is denoted POLD1 c.1786G>A at the cDNA level, p.Val596Ile (V596I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported in a colorectal tumor with microsatellite instability (Shinbrot 2014). POLD1 Val596Ile was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. POLD1 Val596Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the Pol II/Motif A domain (Preston 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLD1 Val596Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480181	SCV000601890	uncertain significance	not specified	2017-06-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000476043	SCV000786451	uncertain significance	Colorectal cancer, susceptibility to, 10	2018-05-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003424018	SCV004118252	uncertain significance	POLD1-related condition	2023-05-02	criteria provided, single submitter	clinical testing	The POLD1 c.1786G>A variant is predicted to result in the amino acid substitution p.Val596Ile. To our knowledge, this variant has not been reported as a germline variant in the literature. However, this variant has been reported as a somatic variant in a colorectal cancer tumor with microsatellite instability (Table S1B - Shinbrot et al. 2014. PubMed ID: 25228659). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50912052-G-A) and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/408030/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.