chr12-132638056-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_006231.4(POLE):c.5636G>A(p.Arg1879His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1879C) 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 -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.5636G>A | p.Arg1879His | missense_variant | 41/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.5636G>A | p.Arg1879His | missense_variant | 41/48 | ||
POLE | XM_011534797.4 | c.4715G>A | p.Arg1572His | missense_variant | 33/40 | ||
POLE | XM_011534802.4 | c.2624G>A | p.Arg875His | missense_variant | 17/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.5636G>A | p.Arg1879His | missense_variant | 41/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251456Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135900
GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461816Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727216
GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74426
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 13, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant not in HGMD or ClinVar. MaxMAF is 0.11% AA not conserved in mammals - His seen in 6 non-mammals. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2016 | This variant is denoted POLE c.5636G>A at the cDNA level, p.Arg1879His (R1879H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Arg1879His was observed with an allele frequency of 0.4% (5/1322) in the African populations in 1000 Genomes. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. POLE Arg1879His occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is not located in a known functional domain (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 Arg1879His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2024 | This alteration is classified as 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 31, 2020 | - - |
Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 25, 2021 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Colorectal cancer, susceptibility to, 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 25, 2023 | The POLE c.5636G>A (p.Arg1879His) missense change has a maximum subpopulation frequency of 0.10% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
POLE-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 30, 2022 | The POLE c.5636G>A variant is predicted to result in the amino acid substitution p.Arg1879His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133214642-C-T) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/403332). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at