Submissions for variant NM_002691.4(POLD1):c.1791C>T (p.Pro597=)

gnomAD frequency: 0.00002  dbSNP: rs138293440

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001080022	SCV000646510	likely benign	Colorectal cancer, susceptibility to, 10	2023-12-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574765	SCV000670922	likely benign	Hereditary cancer-predisposing syndrome	2016-12-09	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.
GeneDx	RCV000842151	SCV000984147	likely benign	not provided	2018-04-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Sema4, Sema4	RCV000574765	SCV002534603	likely benign	Hereditary cancer-predisposing syndrome	2021-03-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268152	SCV002551937	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355779	SCV001550758	benign	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLD1 p.Pro11= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs3218768) as "With Benign allele ", ClinVar (4x as benign by Invitae, GeneDx, Ambry Genetics, Quest Diagnostics Nichols Institute San Juan Capistrano), and LOVD 3.0. The variant was identified in control databases in 937 of 261746 chromosomes (25 homozygous) at a frequency of 0.004, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 913 of 18194 chromosomes (freq: 0.05), Other in 10 of 6104 chromosomes (freq: 0.002), Latino in 4 of 33324 chromosomes (freq: 0.0001), European in 2 of 118794 chromosomes (freq: 0.00002), and South Asian in 8 of 29432 chromosomes (freq: 0.0003); it was not observed in the African, Ashkenazi Jewish, or Finnish populations. The p.Pro11= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.