22-28695243-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_007194.4(CHEK2):c.1260-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000657 in 152,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007194.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
Publications
- CHEK2-related cancer predispositionInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
- Li-Fraumeni syndrome 2Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
- acute myeloid leukemiaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary nonpolyposis colon cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1384696Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 693138
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The c.1260-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 11 of the CHEK2 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration primarily results in a transcript predicted to lead to a protein with an in-frame deletion of two amino acids; however, the exact functional impact of the deleted amino acids is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
This variant causes a G>A nucleotide substitution at the -1 position of intron 11 of the CHEK2 protein. Splice site prediction tools predict the weakening of the canonical acceptor site and strengthening of an in-frame cryptic acceptor, resulting in the loss of two amino acids. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in an individual affected with esophageal adenocarcinoma (PMID: 37507074). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
CHEK2-related cancer predisposition Pathogenic:1
The CHEK2 c.1260-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were identified through this search. This variant is not reported in a region of good sequencing coverage in the Genome Aggregation Database, indicating it is rare. Based on the variant's rarity and the known significance of loss of function variants in the CHEK2 gene, the c.1260-1G>A variant is classified as likely pathogenic for CHEK2-related cancer susceptibility. -
not specified Uncertain:1
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Familial cancer of breast Uncertain:1
This sequence change affects an acceptor splice site in intron 11 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 2 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with esophageal adenocarcinoma (PMID: 37507074). ClinVar contains an entry for this variant (Variation ID: 185068). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 12 (internal data). 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. -
Hereditary breast ovarian cancer syndrome Uncertain:1
According to the ACMG SVI adaptation criteria we chose these criteria: PVS1 (medium pathogenic): PVS1 decision tree as per Tayoun (2018, PMID: 30192042): GT-AG splice sites -->Use of a cryptic splice site preserves reading frame (Splice AI predicts canonical AL & AG at -7bp) --> LoF variants in this exon are not frequent in the general population and exon is present in biologically-relevant transcript(s) --> Variant removes <10% of protein --> Moderate, PM2 (supporting pathogenic): ansent from gnomAD v2; 1x het in gnomAD v3/4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at