12-132672716-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_006231.4(POLE):c.1597G>A(p.Val533Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V533V) 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 -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250626Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135668
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461820Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727202
GnomAD4 genome AF: 0.000158 AC: 24AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74370
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLE p.Val533Met variant was not identified in the literature but was found in dbSNP (ID: rs374140892), ClinVar (classified as a VUS by Invitae and Ambry Genetics) and Cosmic (FATHMM predicted pathogenic; score=0.97). The variant was also identified in control databases in 13 of 282016 chromosomes at a frequency of 0.000046 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 11 of 24814 chromosomes (freq: 0.000443), Ashkenazi Jewish in 1 of 10322 chromosomes (freq: 0.000097) and Latino in 1 of 35400 chromosomes (freq: 0.000028), while the variant was not observed in the East Asian, European (Finnish), European (non-Finnish), Other, and South Asian populations. The p.Val533 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2024 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with cervical, breast, and/or thyroid cancer (PMID: 32098697, 35534704); This variant is associated with the following publications: (PMID: 31240875, 32098697, 36315513, 35534704) - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | - - |
Colorectal cancer, susceptibility to, 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jul 11, 2023 | The POLE c.1597G>A (p.Val533Met) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been observed in a colorectal tumor that did not exhibit a hypermutator phenotype (PMID: 31240875). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
POLE-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 13, 2024 | The POLE c.1597G>A variant is predicted to result in the amino acid substitution p.Val533Met. This variant along with c.6751T>C, p.Phe2251Leu in POLE, as well as pathogenic variants in PIK3CA and PTEN genes was found in dysplastic and invasive tumor components obtained from a cervical cancer specimen (Table 1, Vormittag-Nocito et al. 2020. PubMed ID: 32098697). This variant is reported in 0.044% of alleles in individuals of African descent in gnomAD. In ClinVar, this variant is interpreted as likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/405832/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2024 | The p.V533M variant (also known as c.1597G>A), located in coding exon 15 of the POLE gene, results from a G to A substitution at nucleotide position 1597. The valine at codon 533 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at