22-28694030-A-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007194.4(CHEK2):c.1461+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 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 Likely pathogenic (★★).
Frequency
Consequence
NM_007194.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000139 AC: 2AN: 1438238Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1AN XY: 716380
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change occurs 2 nucleotides after exon 13 of the CHEK2 gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. This variant is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Truncating variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). Also, donor and acceptor splice site variants as usual lead to a loss of protein function (PMID: 16199547). This variant has been described in the international literature in individuals with personal or family history of breast and/or ovarian cancer(PMID:24549055) and an individual undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID:572314). -
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Familial cancer of breast Pathogenic:2
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
This sequence change affects a donor splice site in intron 13 of the CHEK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 24549055, 31159747). ClinVar contains an entry for this variant (Variation ID: 572314). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Breast and/or ovarian cancer Pathogenic:1
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Hereditary cancer-predisposing syndrome Pathogenic:1
The c.1461+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 12 in the CHEK2 gene. This alteration has been identified in a cohort of high-risk breast/ovarian cancer patients (Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at