12-132624741-T-A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_006231.4(POLE):c.6817A>T(p.Thr2273Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000837 in 1,613,164 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. T2273I) has been classified as Uncertain significance.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.6817A>T | p.Thr2273Ser | missense_variant | 49/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6817A>T | p.Thr2273Ser | missense_variant | 49/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00421 AC: 640AN: 151958Hom.: 3 Cov.: 33
GnomAD3 exomes AF: 0.00120 AC: 301AN: 250960Hom.: 5 AF XY: 0.00102 AC XY: 139AN XY: 135720
GnomAD4 exome AF: 0.000487 AC: 711AN: 1461088Hom.: 5 Cov.: 30 AF XY: 0.000400 AC XY: 291AN XY: 726966
GnomAD4 genome ? AF: 0.00420 AC: 639AN: 152076Hom.: 3 Cov.: 33 AF XY: 0.00424 AC XY: 315AN XY: 74358
ClinVar
Submissions by phenotype
not specified Benign:6
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 27, 2018 | Variant summary: POLE c.6817A>T (p.Thr2273Ser) results in a conservative amino acid change in 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 0.0015 in 276634 control chromosomes, predominantly at a frequency of 0.016 within the African subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 1126 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 origin. To our knowledge, no occurrence of c.6817A>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, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 27, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 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 | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 07, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 30, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Colorectal cancer, susceptibility to, 12 Benign:2
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Counsyl | Aug 05, 2016 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 20, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Sep 11, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 04, 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. - |
Carcinoma of colon Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLE p.Thr2273Ser variant was not identified in the literature. The variant was identified in dbSNP (ID: rs73481453) as “With other allele” and ClinVar (classified as benign by Invitae, Ambry Genetics and 4 other submitters; and as likely benign by GeneDx and 1 other submitter). The variant was identified in control databases in 424 (5 homozygous) of 276634 chromosomes at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 385 (5 homozygous) of 23998 chromosomes (freq: 0.02), Other in 5 of 6450 chromosomes (freq: 0.0008), Latino in 28 of 34420 chromosomes (freq: 0.0008), European Non-Finnish in 5 of 126184 chromosomes (freq: 0.00004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, East Asian, or European Finnish populations. The p.Thr2273Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Ser impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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