chr12-132675450-CCTT-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting
The NM_006231.4(POLE):βc.1171_1173delβ(p.Lys391del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. K391K) has been classified as Likely benign.
Frequency
Consequence
NM_006231.4 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.1171_1173del | p.Lys391del | inframe_deletion | 12/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.1171_1173del | p.Lys391del | inframe_deletion | 12/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251416Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135888
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461876Hom.: 0 AF XY: 0.0000633 AC XY: 46AN XY: 727242
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Colorectal cancer, susceptibility to, 12 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 11, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 19, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2022 | This variant, c.1171_1173del, results in the deletion of 1 amino acid(s) of the POLE protein (p.Lys391del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs753999122, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of POLE-related conditions (PMID: 27720647). ClinVar contains an entry for this variant (Variation ID: 240380). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2023 | In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Absent in cases but observed in a control individual in a melanoma case-control study (Pritchard et al., 2018); This variant is associated with the following publications: (PMID: 20951805, 29641532, 27720647) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 31, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 13, 2023 | The c.1171_1173delAAG variant (also known as p.K391del) is located in coding exon 12 of the POLE gene. This variant results from an in-frame AAG deletion at nucleotide positions 1171 to 1173. This results in the in-frame deletion of a lysine at codon 391. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). The deleted amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at