rs528264567
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_006231.4(POLE):c.4411C>T(p.Arg1471Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,614,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1471L) has been classified as Uncertain significance.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.4411C>T | p.Arg1471Cys | missense_variant | 34/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.4411C>T | p.Arg1471Cys | missense_variant | 34/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000835 AC: 21AN: 251470Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135912
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461882Hom.: 0 Cov.: 36 AF XY: 0.0000316 AC XY: 23AN XY: 727240
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152340Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74502
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 10, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1471 of the POLE protein (p.Arg1471Cys). This variant is present in population databases (rs528264567, gnomAD 0.04%). This missense change has been observed in individual(s) with breast cancer and/or clinical features of familial adenomatous polyposis (PMID: 30093976, 34897210). ClinVar contains an entry for this variant (Variation ID: 240513). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with clinical features of familial adenomatous polyposis (FAP) or attenuated FAP and also in an individual with breast cancer (Chan et al., 2018; Park et al., 2022); This variant is associated with the following publications: (PMID: 29320758, 29056344, 34897210, 30093976) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at