Submissions for variant NM_006231.4(POLE):c.3245G>A (p.Arg1082His)

gnomAD frequency: 0.00016  dbSNP: rs201744227

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000484837	SCV000289325	uncertain significance	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1082 of the POLE protein (p.Arg1082His). This variant is present in population databases (rs201744227, gnomAD 0.03%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29987844, 37990341). ClinVar contains an entry for this variant (Variation ID: 240461). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000484837	SCV000568952	uncertain significance	not provided	2024-10-21	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 with ovarian, breast, colon or other cancer (PMID: 28873162, 29987844, 34326862, 36315513, 37990341); This variant is associated with the following publications: (PMID: 29056344, 29987844, 28873162, 34326862, 36315513, 37990341)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484837	SCV000888523	uncertain significance	not provided	2019-01-25	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825438	SCV000966736	uncertain significance	not specified	2018-10-18	criteria provided, single submitter	clinical testing	The p.Arg1082His variant in POLE has not been previously reported in the literat ure in individuals with colorectal cancer but has been reported by other clinica l laboratories in ClinVar (Variation ID: 240461). This variant has also been ide ntified in 33/125928 of European chromosomes by gnomAD (http://gnomad.broadinsti tute.org). Computational prediction tools do not provide support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1082 His variant is uncertain. ACMG/AMP Criteria applied: None applicable.
Baylor Genetics	RCV000232058	SCV001482616	uncertain significance	Colorectal cancer, susceptibility to, 12	2020-11-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mendelics	RCV000758174	SCV002519171	likely benign	Hereditary cancer-predisposing syndrome	2024-04-09	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000825438	SCV002760744	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500792	SCV002813330	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	2021-11-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532926	SCV004116065	uncertain significance	POLE-related disorder	2023-09-20	criteria provided, single submitter	clinical testing	The POLE c.3245G>A variant is predicted to result in the amino acid substitution p.Arg1082His. This variant has been reported as a variant of uncertain significance in individuals with various cancers (Kayser et al. 2018. PubMed ID: 29987844; Bhai et al. 2021. PubMed ID: 34326862; McDonald et al. 2022. PubMed ID: 36315513). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133235911-C-T), and multiple labs classify it as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/240461/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV004776279	SCV005382082	uncertain significance	Neuroepithelial neoplasm		criteria provided, single submitter	research
Ambry Genetics	RCV000758174	SCV005479468	likely benign	Hereditary cancer-predisposing syndrome	2024-08-23	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.
True Health Diagnostics	RCV000758174	SCV000886711	uncertain significance	Hereditary cancer-predisposing syndrome	2018-11-12	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000484837	SCV001740535	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000484837	SCV001808418	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000484837	SCV001918115	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000484837	SCV001969160	likely benign	not provided		no assertion criteria provided	clinical testing