rs368388249
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_007194.4(CHEK2):c.1259+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,612,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007194.4 splice_region, intron
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 |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1259+8A>G | splice_region_variant, intron_variant | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1259+8A>G | splice_region_variant, intron_variant | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000400 AC: 10AN: 249956Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135494
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1460122Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15AN XY: 726536
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74472
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 04, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 10, 2022 | Variant summary: CHEK2 c.1259+8A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 249956 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.00031), allowing no conclusion about variant significance. c.1259+8A>G has been reported in the literature in an individual affected with breast cancer without evidence for causality (example: Ackay_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (2), benign (n=1) and likely Benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2017 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 29, 2021 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at