Submissions for variant NM_006231.4(POLE):c.1015G>A (p.Asp339Asn)

gnomAD frequency: 0.00041  dbSNP: rs149029910

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001582785	SCV000289234	likely benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563592	SCV000671358	likely benign	Hereditary cancer-predisposing syndrome	2022-11-10	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.
GeneDx	RCV001582785	SCV001819188	uncertain significance	not provided	2021-07-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20951805, 27535533, 30968248)
Genetic Services Laboratory, University of Chicago	RCV001818623	SCV002070440	uncertain significance	not specified	2021-11-30	criteria provided, single submitter	clinical testing	DNA sequence analysis of the POLE gene demonstrated a sequence change, c.1015G>A, in exon 10 that results in an amino acid change, p.Asp339Asn. This sequence change has been described in the gnomAD database with a frequency of 0.11% in the African/African American subpopulation (dbSNP rs149029910). The p.Asp339Asn change affects a highly conserved amino acid residue located in a domain of the POLE protein that is known to be functional. The p.Asp339Asn substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with POLE-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asp339Asn change remains unknown at this time.
Mendelics	RCV005235184	SCV002519188	likely benign	Hereditary cancer	2025-02-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Sema4, Sema4	RCV000563592	SCV002538587	likely benign	Hereditary cancer-predisposing syndrome	2020-08-27	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818623	SCV002600813	likely benign	not specified	2022-10-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818623	SCV002760955	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001818623	SCV002773916	benign	not specified	2021-07-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532914	SCV004735781	likely benign	POLE-related disorder	2023-08-09	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).