Submissions for variant NM_006231.4(POLE):c.1347G>A (p.Thr449=)

gnomAD frequency: 0.00094  dbSNP: rs142373951

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000759263	SCV000289251	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000486459	SCV000568884	likely benign	not specified	2018-02-20	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	RCV000492380	SCV000581381	likely benign	Hereditary cancer-predisposing syndrome	2015-07-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
PreventionGenetics, part of Exact Sciences	RCV000486459	SCV000806716	benign	not specified	2016-12-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759263	SCV000888494	benign	not provided	2022-11-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000759263	SCV001148904	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	POLE: BP4, BP7
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000486459	SCV001737898	benign	not specified	2021-06-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759263	SCV002047895	likely benign	not provided	2021-10-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000492380	SCV002536747	benign	Hereditary cancer-predisposing syndrome	2020-09-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000486459	SCV002550186	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000492380	SCV000788160	likely benign	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357614	SCV001553135	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE pThr449T= variant was not identified in the literature. The variant was identified in dbSNP (rs142373951) as “with likely benign allele”, ClinVar (interpreted as "likely benign" by Ambry Genetics and 4 others and "benign" by Invitae and 1 other). The variant was identified in control databases in 302 of 275,634 chromosomes (2 homozygous) at a frequency of 0.001 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 2 of 23,998 chromosomes (freq: 0.00008), Other in 8 of 6452 chromosomes (freq: 0.001), Latino in 5 of 34,410 chromosomes (freq: 0.0001), European in 190 of 126,412 chromosomes (freq: 0.002), Ashkenazi Jewish in 1 of 10,146 chromosomes (freq: 0.0001), Finnish in 93 of 24,582 chromosomes (freq: 0.004), and South Asian in 3 of 30,780 chromosomes (freq: 0.00009); it was not observed in the East Asian population. The p.Thr449= 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 outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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, Academic Medical Center	RCV000759263	SCV001917742	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000759263	SCV001967763	likely benign	not provided		no assertion criteria provided	clinical testing