Submissions for variant NM_006231.4(POLE):c.1645T>C (p.Ser549Pro)

gnomAD frequency: 0.00020  dbSNP: rs115558715

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000484127	SCV000544095	likely benign	not provided	2025-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000484127	SCV000570767	uncertain significance	not provided	2024-10-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals colon or breast cancer (PMID: 25110875, 35264596); This variant is associated with the following publications: (PMID: Krishnan[Abstract], 20951805, 35264596, 25110875, 35534704)
Mendelics	RCV000709274	SCV000838705	uncertain significance	Familial colorectal cancer	2018-07-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268066	SCV002550175	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001086803	SCV004031253	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-07-27	criteria provided, single submitter	clinical testing	The POLE c.1645T>C (p.Ser549Pro) missense change has a maximum subpopulation frequency of 0.085% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics	RCV004943857	SCV005478848	likely benign	Hereditary cancer-predisposing syndrome	2024-07-08	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.