rs5745068
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_006231.4(POLE):c.6494G>A(p.Arg2165His) variant causes a missense change. The variant allele was found at a frequency of 0.00458 in 1,609,618 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts 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. R2165C) 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.6494G>A | p.Arg2165His | missense_variant | 46/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.6494G>A | p.Arg2165His | missense_variant | 46/48 | ||
POLE | XM_011534797.4 | c.5573G>A | p.Arg1858His | missense_variant | 38/40 | ||
POLE | XM_011534802.4 | c.3482G>A | p.Arg1161His | missense_variant | 22/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6494G>A | p.Arg2165His | missense_variant | 46/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00576 AC: 876AN: 152190Hom.: 5 Cov.: 33
GnomAD3 exomes AF: 0.00589 AC: 1432AN: 243000Hom.: 7 AF XY: 0.00643 AC XY: 846AN XY: 131578
GnomAD4 exome AF: 0.00446 AC: 6493AN: 1457310Hom.: 34 Cov.: 32 AF XY: 0.00484 AC XY: 3505AN XY: 724614
GnomAD4 genome ? AF: 0.00574 AC: 875AN: 152308Hom.: 5 Cov.: 33 AF XY: 0.00603 AC XY: 449AN XY: 74466
ClinVar
Submissions by phenotype
not specified Benign:10
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 | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 14, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLE p.Arg2165His variant was identified in 6 of 600 proband chromosomes (frequency: 0.01) from individuals or families with endometrial carcinoma and breast cancer (Wong 2016, Maxwell 2016). The variant was also identified in the following databases: dbSNP (ID: rs5745068) as "With other allele", ClinVar (4x likely benign, 1x benign), and Clinvitae. The variant was not identified in Cosmic or the MutDB database. The variant was identified in control databases in 1538 of 269142 chromosomes (10 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 191 of 23136 chromosomes (freq: 0.008), Other in 48 of 6318 chromosomes (freq: 0.008), Latino in 93 of 33642 chromosomes (freq: 0.003), European in 474 of 122460 chromosomes (freq: 0.004), Ashkenazi Jewish in 117 of 9978 chromosomes (freq: 0.01), East Asian in 180 of 18418 chromosomes (freq: 0.01), Finnish in 8 of 25212 chromosomes (freq: 0.0003), and South Asian in 427 of 29978 chromosomes (freq: 0.01). The p.Arg2165 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2017 | 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, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 07, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 29, 2018 | Variant summary: POLE c.6494G>A (p.Arg2165His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0057 in 269142 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 402 fold above 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 benign. The variant c.6494G>A has been reported in the literature in individuals affected with Colorectal Cancer. These report(s) do not provide unequivocal conclusions about the association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with all laboratories classifying the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 19, 2021 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 05, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | POLE: BS1, BS2 - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 26, 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. - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Sep 29, 2017 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 11, 2021 | - - |
Colorectal cancer, susceptibility to, 12 Benign:2
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Jun 08, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at