rs5744758
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_006231.4(POLE):c.846C>T(p.Pro282=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,613,934 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P282P) has been classified as Likely benign.
Frequency
Consequence
NM_006231.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.846C>T | p.Pro282= | synonymous_variant | 9/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.846C>T | p.Pro282= | synonymous_variant | 9/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00272 AC: 413AN: 152112Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.000823 AC: 207AN: 251440Hom.: 1 AF XY: 0.000670 AC XY: 91AN XY: 135900
GnomAD4 exome AF: 0.000287 AC: 420AN: 1461704Hom.: 3 Cov.: 31 AF XY: 0.000256 AC XY: 186AN XY: 727152
GnomAD4 genome ? AF: 0.00273 AC: 415AN: 152230Hom.: 2 Cov.: 32 AF XY: 0.00263 AC XY: 196AN XY: 74436
ClinVar
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 08, 2018 | Variant summary: The POLE c.846C>T (p.Pro282Pro) variant involves the alteration of a non-conserved nucleotide located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) (InterPro), resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. This variant was found in 282/277164 control chromosomes (2 homozygotes) in gnomAD at a frequency of 0.0010174, which is approximately 72 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 10, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 23, 2018 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 20, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 22, 2015 | 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, no assertion criteria provided | clinical testing | True Health Diagnostics | Oct 04, 2018 | - - |
Colorectal cancer, susceptibility to, 12 Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 14, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at