ClinVar Miner

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

gnomAD frequency: 0.00034  dbSNP: rs113998091
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000478471 SCV000544006 likely benign not provided 2025-02-02 criteria provided, single submitter clinical testing
GeneDx RCV000478471 SCV000569978 uncertain significance not provided 2024-07-23 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: 35264596, 36315513)
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 2025-03-04 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: 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 RCV004539931 SCV004766306 uncertain significance POLE-related disorder 2024-07-30 no assertion criteria provided clinical testing The POLE c.1534G>A variant is predicted to result in the amino acid substitution p.Ala512Thr. This variant has been reported in an individual with breast cancer (Table S3, Guindalini et al. 2022. PubMed ID: 35264596), however it is not known if this variant co-occurred with any known pathogenic variant in other breast cancer-related genes. 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.

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