Submissions for variant NM_002691.4(POLD1):c.2300C>T (p.Ser767Leu)

gnomAD frequency: 0.00001  dbSNP: rs556196668

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485295	SCV000571477	uncertain significance	not provided	2023-01-26	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; This variant is associated with the following publications: (PMID: 29056344)
Invitae	RCV000805603	SCV000945564	uncertain significance	Colorectal cancer, susceptibility to, 10	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 767 of the POLD1 protein (p.Ser767Leu). This variant is present in population databases (rs556196668, gnomAD 0.007%). 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: 422094). 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.
Ambry Genetics	RCV002446935	SCV002734858	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-25	criteria provided, single submitter	clinical testing	The p.S767L variant (also known as c.2300C>T), located in coding exon 18 of the POLD1 gene, results from a C to T substitution at nucleotide position 2300. The serine at codon 767 is replaced by leucine, an amino acid with dissimilar properties. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000485295	SCV002822595	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing