rs1060500855

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006231.4(POLE):​c.2342C>T​(p.Ala781Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,611,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.61
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.2397351).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkuse as main transcriptc.2342C>T p.Ala781Val missense_variant 21/49 ENST00000320574.10 NP_006222.2 Q07864

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.2342C>T p.Ala781Val missense_variant 21/491 NM_006231.4 ENSP00000322570.5 Q07864

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152128
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249450
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135084
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1459358
Hom.:
0
Cov.:
31
AF XY:
0.0000248
AC XY:
18
AN XY:
726088
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152128
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74300
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 781 of the POLE protein (p.Ala781Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 405802). 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 submitterclinical testingGeneDxDec 19, 2019Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (Lek 2016) -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 09, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T;.
Eigen
Benign
0.060
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.0099
T
MetaRNN
Benign
0.24
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L;.
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-2.1
N;N
REVEL
Benign
0.13
Sift
Benign
0.20
T;T
Sift4G
Benign
0.17
T;T
Polyphen
0.23
B;B
Vest4
0.23
MutPred
0.42
Gain of catalytic residue at K776 (P = 0.0047);.;
MVP
0.41
MPC
0.65
ClinPred
0.28
T
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.047
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060500855; hg19: chr12-133242014; COSMIC: COSV57693452; COSMIC: COSV57693452; API