rs879254232
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_006231.4(POLE):c.5792C>T(p.Ser1931Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
POLE
NM_006231.4 missense
NM_006231.4 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 8.01
Genes affected
POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.5792C>T | p.Ser1931Phe | missense_variant | 42/49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.5792C>T | p.Ser1931Phe | missense_variant | 42/48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.4871C>T | p.Ser1624Phe | missense_variant | 34/40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.2780C>T | p.Ser927Phe | missense_variant | 18/24 | XP_011533104.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.5792C>T | p.Ser1931Phe | missense_variant | 42/49 | 1 | NM_006231.4 | ENSP00000322570.5 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461354Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726986
GnomAD4 exome
AF:
AC:
1
AN:
1461354
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
726986
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1931 of the POLE protein (p.Ser1931Phe). This variant is not present in population databases (gnomAD no frequency). 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: 246386). 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 | Feb 05, 2016 | This variant is denoted POLE c.5792C>T at the cDNA level, p.Ser1931Phe (S1931F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Ser1931Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. POLE Ser1931Phe occurs at a position that is not conserved and is not located in a known functional domain (Tahirov 2009, Preston 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLE Ser1931Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 16, 2021 | The p.S1931F variant (also known as c.5792C>T), located in coding exon 42 of the POLE gene, results from a C to T substitution at nucleotide position 5792. The serine at codon 1931 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
P;.
Vest4
MutPred
Gain of catalytic residue at R1932 (P = 0);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at