rs201273415
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_006231.4(POLE):c.5900C>T(p.Ala1967Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,082 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. A1967A) has been classified as Likely benign.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.5900C>T | p.Ala1967Val | missense_variant | 43/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.5900C>T | p.Ala1967Val | missense_variant | 43/48 | ||
POLE | XM_011534797.4 | c.4979C>T | p.Ala1660Val | missense_variant | 35/40 | ||
POLE | XM_011534802.4 | c.2888C>T | p.Ala963Val | missense_variant | 19/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.5900C>T | p.Ala1967Val | missense_variant | 43/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000964 AC: 24AN: 248982Hom.: 0 AF XY: 0.0000965 AC XY: 13AN XY: 134778
GnomAD4 exome AF: 0.0000506 AC: 74AN: 1461786Hom.: 1 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 727196
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1967 of the POLE protein (p.Ala1967Val). This variant is present in population databases (rs201273415, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 246263). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23359684, 25228659, 24265153, 26110843, 28912153, 32546565) - |
POLE-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 23, 2023 | The POLE c.5900C>T variant is predicted to result in the amino acid substitution p.Ala1967Val. To our knowledge, this variant has not been reported in individuals with POLE-related disease. This variant is reported in 0.052% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133210876-G-A) and has conflicting interpretations in ClinVar of uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/246263/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Colorectal cancer, susceptibility to, 12 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 19, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at