Submissions for variant NM_006231.4(POLE):c.4901G>A (p.Arg1634His)

gnomAD frequency: 0.00006  dbSNP: rs760149463

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000767203	SCV000289409	uncertain significance	not provided	2025-01-23	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 1634 of the POLE protein (p.Arg1634His). This variant is present in population databases (rs760149463, gnomAD 0.03%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 240545). 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	RCV000767203	SCV000293818	uncertain significance	not provided	2024-05-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colorectal cancer (PMID: 35534704); This variant is associated with the following publications: (PMID: 31034466, 18772396, 35534704)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236283	SCV000602059	uncertain significance	not specified	2017-05-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765050	SCV000896247	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000226226	SCV001138865	uncertain significance	Colorectal cancer, susceptibility to, 12	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257586	SCV002536868	likely benign	Hereditary cancer-predisposing syndrome	2020-10-23	criteria provided, single submitter	curation
Ambry Genetics	RCV002257586	SCV003675989	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-05	criteria provided, single submitter	clinical testing	The c.4901G>A (p.R1634H) alteration is located in exon 37 (coding exon 37) of the POLE gene. This alteration results from a G to A substitution at nucleotide position 4901, causing the arginine (R) at amino acid position 1634 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect - Invitae Patient Insights Network	RCV003483591	SCV004228652	not provided	Familial colorectal cancer; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 05-03-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.