CHEK2 c.715G>A, p.Glu239Lys
NM_007194.3:c.715G>A
COSM6948821
Population Frequency
0.00849%
Low Frequency
ClinVar Classification
Likely Pathogenic
8 publications
REVEL Score
0.445
Uncertain (Low)
COSMIC Recurrence
2 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
CHEK2
Transcript
NM_007194.4
MANE Select
Total Exons
15
Strand
Reverse (−)
Reference Sequence
NC_000022.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_007194.3 | Alternative | 15 exons | Reverse |
Variant Details
HGVS Notation
NM_007194.3:c.715G>A
Protein Change
E239K
Location
Exon 6
(Exon 6 of 15)
5'
Exon Structure (15 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 239 in gene CHEK2
Alternate Identifiers
COSM6948821
Variant interpretation based on transcript NM_007194.4
Clinical Evidence
Global Frequency
0.00849%
Rare
Highest in Population
European (Finnish)
0.0319%
Low Frequency
Global: 0.00849%
European (Finnish): 0.0319%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 282754
Alt: 24
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00849%, 24/282754 alleles, homozygotes = 0) and at a higher frequency in the European (Finnish) population (MAF= 0.0319%, 8/25064 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
8 publications
Likely Pathogenic
Based on 17 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
8 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (16 clinical laboratories) and as Likely pathogenic (1 clinical laboratories).
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 239 in gene CHEK2
Functional Studies
Summary
The CHEK2 E239K variant has been functionally characterized and demonstrates a damaging effect. It results in reduced Chek2-mediated DNA damage repair in yeast, decreased Chek2 protein expression and phosphorylation in cultured cells, and decreased kinase activity in an in vitro assay. These findings indicate a loss of function for the Chek2 protein associated with this variant.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.445
0.445
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant does not establish it as a null variant and the provided variant type and transcript details are unclear. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence does not include a report of an alternative nucleotide change causing the same amino acid substitution in CHEK2. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. There is no evidence provided regarding de novo occurrence; hence, PS2 is not applied.
PS3
PS3 (Strong)
According to PTEN Pre-processing guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product'. The evidence for CHEK2 E239K demonstrates reduced Chek2-mediated DNA damage repair in yeast, decreased Chek2 protein expression and phosphorylation in cultured cells, and decreased kinase activity in in vitro assays. Therefore, this criterion is applied at Strong strength because the functional studies robustly demonstrate loss of function.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals is significantly increased compared with controls'. There is no case–control data provided to support increased prevalence. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. There is no specific evidence provided that this variant is located in such a domain. Therefore, PM1 is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The variant has an extremely low allele frequency (MAF = 0.00849% in gnomAD and even at a slightly higher frequency in some populations, remaining below thresholds) and no homozygotes, supporting its rarity. Therefore, PM2 is applied at Moderate strength.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders)'. There is no evidence provided of this variant being detected in trans with another pathogenic variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. There is no evidence that this variant causes a protein length change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. There is no supporting evidence that another pathogenic missense change at this residue has been reported. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. There is no evidence to suggest this variant is de novo. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. There is no familial segregation data provided. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. Although CHEK2 is known for missense variants, the available data does not sufficiently support applying this criterion independently. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product'. The in silico predictions show a REVEL score of 0.45 and SpliceAI scores of 0, which do not support a deleterious effect. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history is highly specific for a disease with a single genetic etiology'. There is no phenotype or family history data provided in the assessment. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation'. The variant is reported in ClinVar with discrepant classifications (most as Uncertain Significance and one as Likely Pathogenic), and a reputable source has listed it as Likely Pathogenic. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder'. The reported minor allele frequency is very low, which does not meet the BA1 threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The allele frequency for this variant is below typical population frequency thresholds for benign variants. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. There is no evidence provided showing the variant in healthy individuals in a manner that would indicate lack of pathogenicity. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The functional studies indicate a damaging effect on CHEK2 activity, so BS3 is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. There is no segregation analysis data provided. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which primarily truncating variants are known to cause disease'. There is no evidence to specifically favor BP1 for CHEK2 in this case. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. There is no evidence provided for such observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. There is no evidence that this variant falls within a repetitive region, so BP3 is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The computational analyses, including a REVEL score of 0.45 (below the threshold for pathogenicity) and SpliceAI scores of 0, support no deleterious impact. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. There is no evidence of an alternate molecular cause that would argue for BP5. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. Although there is discrepant ClinVar data, the reputable source in this case leans towards Likely Pathogenic, thus BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. This variant results in a missense change (E239K) and is not synonymous. Therefore, BP7 is not applied.