rs121908702
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007194.4(CHEK2):c.715G>T(p.Glu239*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007194.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251364Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135866
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461700Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 727142
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74302
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:3
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This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
This sequence change creates a premature translational stop signal (p.Glu239*) 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 (rs121908702, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with sporadic prostate cancer (PMID: 12533788). ClinVar contains an entry for this variant (Variation ID: 5599). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 6 of the CHEK2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with prostate cancer (PMID: 12533788). This variant has been identified in 2/251364 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.E239* pathogenic mutation (also known as c.715G>T), located in coding exon 5 of the CHEK2 gene, results from a G to T substitution at nucleotide position 715. This changes the amino acid from a glutamic acid to a stop codon within coding exon 5. This variant has been reported in a single individual with a sporadic prostate cancer, and was not identified in any of the 423 controls (Dong X, Am. J. Hum. Genet. 2003 Feb; 72(2):270-80). In addition to the clinical data presented in the literature, 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. -
Colorectal cancer Pathogenic:1
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not provided Pathogenic:1
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as c.844G>T, p.Glu282Ter; Observed in individuals with prostate cancer (Dong 2003); This variant is associated with the following publications: (PMID: 30305041, 12533788, 25525159, 31589614, 32906215) -
Malignant tumor of prostate Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at