chr12-132632697-G-A
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_006231.4(POLE):c.6103C>T(p.Gln2035*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006231.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- POLE-related polyposis and colorectal cancer syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- colorectal cancer, susceptibility to, 12Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
- facial dysmorphism-immunodeficiency-livedo-short stature syndromeInheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
- intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiencyInheritance: AR Classification: STRONG Submitted by: G2P
- IMAGe syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Polymerase proofreading-related adenomatous polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6103C>T | p.Gln2035* | stop_gained | Exon 44 of 49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.6103C>T | p.Gln2035* | stop_gained | Exon 44 of 48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.5182C>T | p.Gln1728* | stop_gained | Exon 36 of 40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.3091C>T | p.Gln1031* | stop_gained | Exon 20 of 24 | XP_011533104.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000400 AC: 1AN: 250104 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461720Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727158 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gln2035*) in the POLE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). This variant is present in population databases (rs757478410, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 29625052). ClinVar contains an entry for this variant (Variation ID: 577590). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.Q2035* variant (also known as c.6103C>T), located in coding exon 44 of the POLE gene, results from a C to T substitution at nucleotide position 6103. This changes the amino acid from a glutamine to a stop codon within coding exon 44. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants subject to nonsense mediated decay (NMD) in POLE are known to cause POLE deficiency; however, such associations with POLE-related polymerase proofreading-associated polyposis (PPAP) have not been reported. Based on the supporting evidence, this alteration is pathogenic for POLE deficiency; however, the association of this alteration with POLE-related polymerase proofreading-associated polyposis (PPAP) is unknown. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at