rs786202122
Variant summary
Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS2_Supporting
The NM_007194.4(CHEK2):c.1011C>A(p.Tyr337*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 1,454,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007194.4 stop_gained, splice_region
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: Pathogenic. The variant received 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD2 exomes AF: 0.00000797 AC: 2AN: 251042 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000894 AC: 13AN: 1454124Hom.: 0 Cov.: 28 AF XY: 0.00000829 AC XY: 6AN XY: 723976 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
This pathogenic variant is denoted CHEK2 c.1011C>A at the cDNA level and p.Tyr337Ter (Y337X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual undergoing multi-gene panel testing (LaDuca 2017). This variant is considered pathogenic. -
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PP5, PM2, PVS1 -
Familial cancer of breast Pathogenic:3
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This sequence change creates a premature translational stop signal (p.Tyr337*) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs760502479, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185370). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 10 of the CHEK2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with CHEK2-related disorders in the literature. This variant has been identified in 2/251042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
The p.Y337* pathogenic mutation (also known as c.1011C>A), located in coding exon 9 of the CHEK2 gene, results from a C to A substitution at nucleotide position 1011. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at