Submissions for variant NM_006231.4(POLE):c.431A>G (p.His144Arg)

gnomAD frequency: 0.00009  dbSNP: rs755709875

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001284215	SCV000544002	uncertain significance	not provided	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 144 of the POLE protein (p.His144Arg). This variant is present in population databases (rs755709875, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 405687). 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 expected to disrupt POLE protein function with a positive 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.
Ambry Genetics	RCV000563876	SCV000671272	uncertain significance	Hereditary cancer-predisposing syndrome	2015-07-01	criteria provided, single submitter	clinical testing	The p.H144R variant (also known as c.431A>G), located in coding exon 6 of the POLE gene, results from an A to G substitution at nucleotide position 431. The histidine at codon 144 is replaced by arginine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.H144R remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002480361	SCV000894736	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	2023-12-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826023	SCV000967512	uncertain significance	not specified	2018-08-14	criteria provided, single submitter	clinical testing	The p.His144Arg variant in POLE has not been previously reported in individuals with colorectal cancer but has been reported by other clinical laboratories in C linVar (Variation ID: 405687). It has also been identified in 3/30758 South Asia n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; dbSNP rs755709875). Computational prediction tools and conservation analysis suggest that the p.His144Arg variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, t he clinical significance of the p.His144Arg variant is uncertain. ACMG/AMP Crite ria applied: PP3, PM2.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284215	SCV001469877	uncertain significance	not provided	2020-03-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001284215	SCV001776613	uncertain significance	not provided	2024-08-07	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast/ovarian cancer, colorectal cancer and/or polyps cancer (PMID: 29212164, 32522261, 35980532); 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: 32522261, 29212164, 35980532)
MGZ Medical Genetics Center	RCV000476907	SCV002581920	uncertain significance	Colorectal cancer, susceptibility to, 12	2021-08-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001284215	SCV005074480	uncertain significance	not provided	2024-06-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000826023	SCV005089997	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001284215	SCV005192074	uncertain significance	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV001284215	SCV005408433	uncertain significance	not provided	2024-04-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004533156	SCV004720229	uncertain significance	POLE-related disorder	2023-12-11	no assertion criteria provided	clinical testing	The POLE c.431A>G variant is predicted to result in the amino acid substitution p.His144Arg. This variant was identified in an individual affected with colorectal cancer whose tumor was microsatellite stable, but the variant was classified as uncertain (Table S3, Raskin et al. 2017. PubMed ID: 29212164). This variant was also described in an individual who underwent hereditary cancer testing; however, other variants of uncertain significance in other genes were also present (Velaquez et al. 2020. PubMed ID: 32522261, Table S1). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD and is classified in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/405687/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.