Submissions for variant NM_002691.4(POLD1):c.2326C>T (p.Arg776Trp)

gnomAD frequency: 0.00006  dbSNP: rs780138978

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000227620	SCV000287566	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 tryptophan, which is neutral and slightly polar, at codon 776 of the POLD1 protein (p.Arg776Trp). This variant is present in population databases (rs780138978, gnomAD 0.01%). 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: 239284). 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	RCV000657108	SCV000569140	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a control individual reporting no personal or family history of colorectal cancer (Arora et al., 2015); This variant is associated with the following publications: (PMID: 29917049, 31422818, 20951805, 26344056)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000481293	SCV000712546	uncertain significance	not specified	2016-11-15	criteria provided, single submitter	clinical testing	The p.Arg776Trp variant in POLD1 has not been previously reported in individuals with colorectal cancer but has been identified in 1/6594 of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs780138978). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg776Trp variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000481293	SCV001362685	likely benign	not specified	2019-06-20	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.2326C>T (p.Arg776Trp) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 248910 control chromosomes. The observed variant frequency is approximately 5.37 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. c.2326C>T has been reported in the literature in individuals control individual(s) (Arora_2015) and in breast tumor tissue (Doisy_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
True Health Diagnostics	RCV000664282	SCV000788139	uncertain significance	Hereditary cancer-predisposing syndrome	2017-08-14	no assertion criteria provided	clinical testing