Submissions for variant NM_002691.4(POLD1):c.1665C>T (p.Val555=)

gnomAD frequency: 0.00053  dbSNP: rs150238541

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001082021	SCV000287529	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000439741	SCV000520753	likely benign	not specified	2017-12-28	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	RCV000574633	SCV000670902	likely benign	Hereditary cancer-predisposing syndrome	2015-06-18	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	RCV000439741	SCV000806472	benign	not specified	2017-01-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759940	SCV000889655	benign	not provided	2018-10-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000759940	SCV001152029	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	POLD1: BP4, BP7
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000439741	SCV001159617	benign	not specified	2019-04-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000439741	SCV002065991	likely benign	not specified	2021-01-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000574633	SCV002534600	benign	Hereditary cancer-predisposing syndrome	2020-10-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000439741	SCV002551921	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000574633	SCV000805285	likely benign	Hereditary cancer-predisposing syndrome	2018-04-06	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354171	SCV001548715	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The POLD1 p.Val555= variant was not identified in the literature. The variant was identified in dbSNP (rs150238541) as “with likely benign allele” and ClinVar (classified as likely benign by Ambry Genetics, GeneDx, True Health Diagnostics and 2 other submitters; and as benign by Invitae and Prevention Genetics). The variant was identified in control databases in 206 of 279,020 chromosomes (2 homozygous) at a frequency of 0.0007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 43 of 30,490 chromosomes (freq: 0.001), European in 142 of 126,522 chromosomes (freq: 0.001), Other in 4 of 7138 chromosomes (freq: 0.0006), Finnish in 13 of 24,740 chromosomes (freq: 0.0005), Ashkenazi Jewish in 1 of 10,192 chromosomes (freq: 0.0001), African in 2 of 24,900 chromosomes (freq: 0.00008), and Latino in 1 of 35,130 chromosomes (freq: 0.00003), while it was not observed in the East Asian population. The p.Val555= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000759940	SCV001973940	likely benign	not provided		no assertion criteria provided	clinical testing