Submissions for variant NM_002691.4(POLD1):c.583C>T (p.Arg195Ter)

gnomAD frequency: 0.00001  dbSNP: rs377690809

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231988	SCV000287639	likely benign	Colorectal cancer, susceptibility to, 10	2023-12-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000231988	SCV000489130	uncertain significance	Colorectal cancer, susceptibility to, 10	2016-08-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000479381	SCV000571819	uncertain significance	not provided	2023-04-19	criteria provided, single submitter	clinical testing	Segregates with disease in affected individuals in the literature, but also identified in several control subjects without history of colorectal cancer or polyps (Rosner et al., 2018); Some missense variants in POLD1 have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP); however, there are no data at this time to support that loss-of-function variants confer the same cancer risks; This variant is associated with the following publications: (PMID: 25986922, 33809179, 30086056, 23263490)
Ambry Genetics	RCV000576035	SCV000671025	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-28	criteria provided, single submitter	clinical testing	The p.R195* variant (also known as c.583C>T), located in coding exon 4 of the POLD1 gene, results from a C to T substitution at nucleotide position 583. This changes the amino acid from an arginine to a stop codon within coding exon 4. In one study, this alteration was detected in 1/132 Jewish patients with colorectal adenomas and/or early-onset, mismatch repair proficient colorectal cancer as well as in 5/5685 control subjects without colorectal adenomas or cancer (Rosner G et al. Dis. Colon Rectum, 2018 09;61:1073-1079). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of POLD1 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000479381	SCV001502262	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	POLD1: PP3
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000479381	SCV002010548	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000576035	SCV002534691	likely benign	Hereditary cancer-predisposing syndrome	2021-01-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465586	SCV002761046	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing