Submissions for variant NM_006231.4(POLE):c.4172C>G (p.Ser1391Cys)

gnomAD frequency: 0.00001  dbSNP: rs149145495

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236163	SCV000293875	uncertain significance	not provided	2024-09-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000236163	SCV000653271	uncertain significance	not provided	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1391 of the POLE protein (p.Ser1391Cys). This variant is present in population databases (rs149145495, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 246358). 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.
Fulgent Genetics, Fulgent Genetics	RCV000765059	SCV000896256	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002327166	SCV002630310	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-30	criteria provided, single submitter	clinical testing	The p.S1391C variant (also known as c.4172C>G), located in coding exon 33 of the POLE gene, results from a C to G substitution at nucleotide position 4172. The serine at codon 1391 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005008213	SCV005633705	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	2024-03-29	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483597	SCV004228920	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 03-04-2021 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.