NM_001274.5:c.709G>T (p.Ala237Ser) in CHEK1 is a missense variant with extremely low population frequency (1/1,595,844 alleles in gnomAD v4.1; PM2 at supporting level).1 Multiple computational predictors uniformly suggest a benign effect: REVEL 0.067, BayesDel -0.406, and SpliceAI max delta 0.02 (BP4 at supporting benign level).2 CHEK1 germline disease is mediated by loss-of-function via truncating variants; a pathogenic splice variant (c.613+2T>C) causing kinase domain truncation has been reported in familial cancer (PMID:38686193). As a missense variant in a gene where truncation is the established disease mechanism, BP1 applies at supporting benign level.3 By generic ACMG/AMP 2015 combination rules (PMID:25741868), two supporting benign criteria (BP1, BP4) with one supporting pathogenic criterion (PM2) yields a classification of Likely Benign.4
CHEK1
Final classification
Likely Benign
CHEK1 c.709G>T · p.Ala237Ser
CHEK1
NM_001274.5:c.709G>T (p.Ala237Ser) in CHEK1 is a missense variant with extremely low population frequency (1/1,595,844 alleles in gnomAD v4.1; PM2 at supporting level).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP1 supporting benign, BP4 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP1BP4
Likely Benign
CHEK1 c.709G>T
PM2 + BP1 + BP4
→
Likely Benign
Gene diagram
· NM_001274.5 · variants mapped to exon structure
CHEK1
NM_001274.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 20 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_001274.5:c.709G>T is extremely rare in population databases. It is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and present in only 1 of 1,595,844 alleles (AF=6.27e-7; 0.00006%) in gnomAD v4.1, with zero homozygotes. This is well below the 0.1% PM2 threshold for non-VCEP adjudication.
gnomAD v2.1: absent.gnomAD v4.1: 1/1595
✓
BP1
supporting
Benign
BP1 applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. CHEK1 germline disease is mediated by loss-of-function via truncating variants; a pathogenic germline splice variant (c.613+2T>C) causing kinase domain truncation has been reported in a family with multiple cancers (PMID:38686193). The variant under review, p.Ala237Ser, is a missense change in a gene where truncation is the established disease mechanism.
CHEK1 germline disease mechanism is loss-of-function via truncating variants.Pathogenic CHEK1 c.613+2T>C splice variant (PMID:38686193) confirmed as truncating LoF allele causing familial cancer.
✓
BP4
supporting
Benign
BP4 requires multiple lines of computational evidence suggesting no impact on gene product. REVEL score is 0.067 (strongly predictive of benign), BayesDel score is -0.406 (predictive of benign), and SpliceAI delta score is 0.02 (no predicted splicing impact). Three independent computational predictors uniformly support a benign interpretation.
REVEL: 0.067 (benign prediction).BayesDel: -0.406 (benign prediction).SpliceAI max delta: 0.02 (no splice impact predicted).
Assessed · not applied
Pathogenic
PS1
PS1 requires a different nucleotide change at the same position that results in the same amino acid change, with the other variant established as pathogenic.
PS2
PS2 requires a de novo observation with confirmed maternity and paternity.
PS3
PS3 requires well-established functional studies demonstrating a damaging effect.
PS4
PS4 requires statistically significant enrichment of the variant in affected individuals compared to controls.
PM1
PM1 requires location in a mutational hotspot or well-established critical functional domain without benign variation.
PM5
PM5 requires a different pathogenic missense change at the same codon.
PM6
PM6 requires a de novo observation without confirmed maternity and paternity.
PP1
PP1 requires cosegregation with disease in multiple affected family members.
PP2
PP2 requires a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP3
PP3 requires multiple lines of computational evidence supporting a deleterious effect.
PP4
PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology.
PP5
PP5 requires a reputable source to have classified the variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >1% in population databases.
BS1
BS1 requires an allele frequency >0.3% in population databases (non-VCEP cutoff).
BS2
BS2 requires observation in a healthy adult individual for a fully penetrant disorder (in homozygous state, or in hemizygous/dominant state at frequency inconsistent with disease penetrance).
BS3
BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing.
BS4
BS4 requires lack of cosegregation with disease in affected family members.
BP2
BP2 requires observation in trans with a pathogenic dominant variant or in cis with a pathogenic recessive variant.
BP5
BP5 requires the variant to be found in a case with an alternate molecular basis for disease.
BP6
BP6 requires a reputable source to have classified the variant as benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.26628e-07; MAF= 0.00006%, 1/1595844 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.54762e-07; MAF= 0.00009%, 1/1169916 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.3e-05%
· 1 / 1,595,844
0 hom
0 hom
European (non-Finnish) 1 / 1,169,916 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.067. BayesDel score = -0.405592.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CHEK1, an intracellular kinase, is overexpressed in various solid and hematologic malignancies.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links