Submissions for variant NM_006231.4(POLE):c.1323G>A (p.Pro441=)

gnomAD frequency: 0.00106  dbSNP: rs116573514

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000586478	SCV000289250	benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000422545	SCV000517992	benign	not specified	2018-02-12	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.
Ambry Genetics	RCV000570202	SCV000671236	benign	Hereditary cancer-predisposing syndrome	2015-07-02	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586478	SCV000698660	benign	not provided	2017-07-28	criteria provided, single submitter	clinical testing	Variant summary: The POLE c.1323G>A (p.Pro441Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 424/121124 control chromosomes (15 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.047923 (413/8618). This frequency is about 3374 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000422545	SCV000806714	benign	not specified	2017-07-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000422545	SCV000888492	benign	not specified	2020-08-04	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000422545	SCV002071572	benign	not specified	2019-04-25	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000422545	SCV002760899	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000570202	SCV000805293	likely benign	Hereditary cancer-predisposing syndrome	2018-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354531	SCV001549173	benign	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLE p.Pro441= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs116573514) as "With Benign allele ", ClinVar (classified as benign in Invitae, GeneDx, Ambry Genetics and two clinical laboratories), and in Cosmic (1x in Large intestine), databases. The variant was identified in control databases in 834 of 276646 chromosomes (18 homozygous) at a frequency of 0.003 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: African in 1 of 24014 chromosomes (freq: 0.00004), Other in 6 of 6460 chromosomes (freq: 0.0009), Latino in 1 of 34414 chromosomes (freq: 0.00003), European in 8 of 126608 chromosomes (freq: 0.00006), East Asian in 802 of 18866 chromosomes (freq: 0.04), and South Asian in 16 of 30782 chromosomes (freq: 0.0005), while the variant was not observed in the Ashkenazi Jewish, and Finnish, populations. The p.Pro441= 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000422545	SCV001809229	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000422545	SCV001925658	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000422545	SCV001958345	benign	not specified		no assertion criteria provided	clinical testing