rs5744800
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_006231.4(POLE):c.2089C>T(p.Pro697Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,612,760 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P697A) has been classified as Likely benign.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.2089C>T | p.Pro697Ser | missense_variant | 19/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.2089C>T | p.Pro697Ser | missense_variant | 19/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00428 AC: 651AN: 152194Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00100 AC: 251AN: 250172Hom.: 3 AF XY: 0.000769 AC XY: 104AN XY: 135184
GnomAD4 exome AF: 0.000481 AC: 703AN: 1460448Hom.: 7 Cov.: 31 AF XY: 0.000441 AC XY: 320AN XY: 726394
GnomAD4 genome ? AF: 0.00431 AC: 656AN: 152312Hom.: 4 Cov.: 32 AF XY: 0.00427 AC XY: 318AN XY: 74470
ClinVar
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 08, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 26, 2019 | Variant summary: POLE c.2089C>T (p.Pro697Ser) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 250172 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 845 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2089C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 29, 2017 | - - |
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jul 12, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 11, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2015 | This 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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 17, 2020 | - - |
Colorectal cancer, susceptibility to, 12 Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLE p.Pro697Ser variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from individuals with advanced cancer (Mandelker 2017). The variant was identified in dbSNP (rs5744800) as “with uncertain significance, other allele” and ClinVar (classified as benign by Invitae, GeneDx, PreventionGenetics and Quest Diagnostics; and as likely benign by Ambry Genetics, Children's Mercy Hospital and 1 other submitter). The variant was identified in control databases in 384 of 281,564 chromosomes (4 homozygous) at a frequency of 0.001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 331 of 24,940 chromosomes (freq: 0.01, increasing the likelihood this could be a low frequency benign variant), Latino in 36 of 35,200 chromosomes (freq: 0.001), Other in 3 of 7170 chromosomes (freq: 0.004), South Asian in 6 of 30,394 chromosomes (freq: 0.0002), European in 7 of 128,630 chromosomes (freq: 0.00005), and East Asian in 1 of 19,892 chromosomes (freq: 0.00005); it was not observed in the Ashkenazi Jewish or Finnish populations. The p.Pro697 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at