Submissions for variant NM_006231.4(POLE):c.1534G>A (p.Ala512Thr)

gnomAD frequency: 0.00034  dbSNP: rs113998091

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000478471	SCV000544006	likely benign	not provided	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000478471	SCV000569978	uncertain significance	not provided	2023-10-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36315513, 35264596)
Mendelics	RCV000709275	SCV000838706	uncertain significance	Familial colorectal cancer	2018-07-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001292658	SCV001481258	uncertain significance	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-11-18	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV002257689	SCV002536755	likely benign	Hereditary cancer-predisposing syndrome	2021-02-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268065	SCV002550178	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002257689	SCV002703900	likely benign	Hereditary cancer-predisposing syndrome	2022-10-22	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	RCV003942472	SCV004766306	uncertain significance	POLE-related condition	2023-12-26	criteria provided, single submitter	clinical testing	The POLE c.1534G>A variant is predicted to result in the amino acid substitution p.Ala512Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.14% of alleles in individuals of African descent in gnomAD, which may be too frequent to be an undocumented pathogenic variant. This variant has been interpreted as both uncertain and likely benign in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/405691). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.