Submissions for variant NM_002691.4(POLD1):c.624G>A (p.Pro208=)

gnomAD frequency: 0.00025  dbSNP: rs78996304

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001083204	SCV000287643	benign	Colorectal cancer, susceptibility to, 10	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000428100	SCV000531263	likely benign	not specified	2018-02-15	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.
Ambry Genetics	RCV000561881	SCV000670948	likely benign	Hereditary cancer-predisposing syndrome	2015-08-31	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.
PreventionGenetics, part of Exact Sciences	RCV000428100	SCV000806554	benign	not specified	2017-04-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759246	SCV000888473	benign	not provided	2017-09-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561881	SCV002534693	benign	Hereditary cancer-predisposing syndrome	2021-03-05	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001083204	SCV004016654	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356402	SCV001551561	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Pro208= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs78996304) “With Likely benign allele” and ClinVar (classified benign by Invitae and Prevention Genetics; and likely benign by GeneDx and Ambry Genetics). The variant was identified in control databases in 88 of 259686 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 1 of 23782 chromosomes (freq: 0.00004), Other in 1 of 6016 chromosomes (freq: 0.0002), European Non-Finnish in 10 of 118560 chromosomes (freq: 0.00008), East Asian in 70 of 18568 chromosomes (freq: 0.004), European Finnish in 5 of 24690 chromosomes (freq: 0.0002), and South Asian in 1 of 27188 chromosomes (freq: 0.00004) while not observed in the Latino and Ashkenazi Jewish. The p.Pro208= 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) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.