Submissions for variant NM_002691.4(POLD1):c.13C>T (p.Arg5Trp)

gnomAD frequency: 0.00038  dbSNP: rs9282830

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079499	SCV000287516	likely benign	Colorectal cancer, susceptibility to, 10	2024-01-27	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000732271	SCV000860198	uncertain significance	not provided	2018-03-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000732271	SCV001134626	benign	not provided	2019-07-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000732271	SCV001790019	uncertain significance	not provided	2021-03-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Genetic Services Laboratory, University of Chicago	RCV001818598	SCV002070050	uncertain significance	not specified	2020-01-03	criteria provided, single submitter	clinical testing	DNA sequence analysis of the POLD1 gene demonstrated a sequence change, c.13C>T, in exon 2 that results in an amino acid change, p.Arg5Trp. This sequence change does not appear to have been previously described in patients with POLD1-related disorders and has been described in the gnomAD database with a frequency of 0.10% in African populations (dbSNP rs9282830). The p.Arg5Trp change affects a highly conserved amino acid residue located in a domain of the POLD1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg5Trp substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg5Trp change remains unknown at this time.
Sema4, Sema4	RCV002257545	SCV002534582	likely benign	Hereditary cancer-predisposing syndrome	2020-10-09	criteria provided, single submitter	curation
Ambry Genetics	RCV002257545	SCV003909062	likely benign	Hereditary cancer-predisposing syndrome	2022-11-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV004541392	SCV004785453	likely benign	POLD1-related disorder	2023-06-16	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).