Submissions for variant NM_002691.4(POLD1):c.1562G>A (p.Arg521Gln)

gnomAD frequency: 0.00006  dbSNP: rs143076166

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000234172	SCV000287525	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 521 of the POLD1 protein (p.Arg521Gln). This variant is present in population databases (rs143076166, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 26133394). ClinVar contains an entry for this variant (Variation ID: 239244). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000657104	SCV000293778	uncertain significance	not provided	2023-03-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in individuals with colorectal cancer (Bellido et al., 2016; Mur et al., 2020); This variant is associated with the following publications: (PMID: 32792570, 26133394, 32041611, 33809179, 20951805)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657104	SCV000601882	uncertain significance	not provided	2019-07-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574111	SCV000670976	likely benign	Hereditary cancer-predisposing syndrome	2020-01-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
CSER _CC_NCGL, University of Washington	RCV000590937	SCV000700093	uncertain significance	Colorectal cancer	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 37 year old female diagnosed with colon cancer at age 36. Patient also has a likely pathogenic variant in MSH2. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Sema4, Sema4	RCV000574111	SCV002534594	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267983	SCV002551919	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000234172	SCV000493784	uncertain significance	Colorectal cancer, susceptibility to, 10	2015-09-26	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000574111	SCV000788130	uncertain significance	Hereditary cancer-predisposing syndrome	2017-11-17	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000234172	SCV002075202	not provided	Colorectal cancer, susceptibility to, 10		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 03-18-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect - Invitae Patient Insights Network	RCV003483586	SCV004228825	not provided	Familial colorectal cancer; Mandibular hypoplasia-deafness-progeroid syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-12-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.