rs139075637
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_006231.4(POLE):c.861T>A(p.Asp287Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,080 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00116 AC: 176AN: 152176Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000859 AC: 216AN: 251450Hom.: 0 AF XY: 0.000758 AC XY: 103AN XY: 135908
GnomAD4 exome AF: 0.00137 AC: 1999AN: 1461786Hom.: 3 Cov.: 31 AF XY: 0.00130 AC XY: 942AN XY: 727194
GnomAD4 genome AF: 0.00116 AC: 176AN: 152294Hom.: 1 Cov.: 32 AF XY: 0.00114 AC XY: 85AN XY: 74472
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4Other:1
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POLE: BS1 -
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This variant is associated with the following publications: (PMID: 26648449, 30374176, 30680046, 30971823, 30414346, 29454559, 29120461, 29185122, 28873162, 27720647, 27153395, 25224212, 26251183) -
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Colorectal cancer, susceptibility to, 12 Uncertain:3Benign:1Other:1
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
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The POLE variant designated as NM_006231.2:c.861T>A (p.Asp287Glu) is classified as likely benign. This variant has been reported at a frequency of over 1 in 400 individuals in individuals with European non-Finnish ancestry (exac.broadinstitute.org). Variants present at this population frequency are unlikely to be associated with high penetrance hereditary cancer risk. Cosegregation analysis of one observed family was performed and shows a likelihood ratio of pathogenicity of 0.98 to 1 (Thompson, et al., 2003, PMID:2900794). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter POLE function or modify cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -
Variant interpreted as Uncertain significance and reported on 12-21-2015 by Lab Ambry. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
not specified Uncertain:2Benign:1
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DNA sequence analysis of the POLE gene demonstrated a sequence change, c.861T>A, in exon 9 that results in an amino acid change, p.Asp287Glu. This sequence change has been described in the gnomAD database with a frequency of 0.18% in the European sub-population (dbSNP rs139075637). The p.Asp287Glu change has been reported in one suspected Lynch syndrome patient (PMID: 26648449) and nine melanoma patients (PMID: 30414346). This sequence change has also been reported in three families with cutaneous malignant melanoma; however, incomplete segregation with disease was observed (PMID: 26251183). The p.Asp287Glu change affects a highly conserved amino acid residue located in a domain of the POLE protein that is known to be functional. The p.Asp287Glu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp287Glu change remains unknown at this time. -
Variant summary: POLE c.861T>A (p.Asp287Glu) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 277192 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 120-folds higher then 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 Non-Finnish European origin. c.861T>A has been reported in the literature in individuals affected with cutaneous malignant melanoma, endometrial cancer and Lynch Syndrome (Aoude_2015, Billingsley_2015, Jansen_2016, Potjer_2018). Two families published by Auode_2015 indicate the variant did not segregate with disease, along with Jansen_2016 reporting a patient with the variant of interest, who had two MLH1 pathogenic somatic variants, c.208-1G>A and c.440_447del. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) predominantly cite the variant as uncertain significance, while two cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
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. -
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Colorectal cancer Uncertain:1
Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 32 year old male with gastric cancer, bladder cancer and colon polyps. Family history of gastric cancer and colon polyps. Patient also has a pathogenic variant in CDH1. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -
POLE-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary cancer Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at