NM_001274.5:c.709G>T

CHEK1 · NP_001265.2:p.(Ala237Ser) · NM_001274.5

GRCh37: chr11:125505419 G>T · GRCh38: chr11:125635524 G>T

Gene: CHEK1 Transcript: NM_001274.5

Final call

Likely Benign

PM2 supporting BP1 supporting benign BP4 supporting benign

Variant details

Gene

CHEK1

Transcript

NM_001274.5

Protein

NP_001265.2:p.(Ala237Ser)

gnomAD AF

6.266276653607746e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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).

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_001274.5:c.709G>T is a missense variant (p.Ala237Ser) and does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). PVS1 is not applicable to missense variants under generic ACMG/AMP framework.	pvs1_generic_framework
PS1	Not met	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. No such variant has been reported for codon 237 of CHEK1.
PS2	Not met	PS2 requires a de novo observation with confirmed maternity and paternity. No de novo data are available for NM_001274.5:c.709G>T.
PS3	Not met	PS3 requires well-established functional studies demonstrating a damaging effect. No variant-specific functional data exist for NM_001274.5:c.709G>T. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. Computational predictors (REVEL 0.067, BayesDel -0.406) are benign, not supportive of a damaging effect.	oncokb revel bayesdel
PS4	Not met	PS4 requires statistically significant enrichment of the variant in affected individuals compared to controls. The variant is absent from ClinVar and has not been reported in any case-control studies. The single allele in gnomAD v4.1 provides no disease-association signal.	gnomad_v4 clinvar
PS5	Not met	PS5 requires a different pathogenic variant at the same amino acid position classified by a reputable source. PM5 candidate search identified no pathogenic missense comparators at codon 237 (p.Ala237) of CHEK1.	pm5_candidates
PM1	Not met	PM1 requires location in a mutational hotspot or well-established critical functional domain without benign variation. Residue Ala237 is not a statistically significant hotspot per cancerhotspots.org. While Ala237 lies within the CHEK1 kinase domain, no domain-level PM1 framework has been established for CHEK1 in the absence of a VCEP, and sparse literature evidence alone is insufficient to apply generic PM1.
PM2	Met	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 gnomad_v4 gnomad_canada
PM3	N/A	PM3 applies to recessive disorders with a pathogenic variant in trans. CHEK1-associated cancer predisposition is not established as a recessive condition, and no trans data are available.
PM4	N/A	PM4 applies to non-repeat in-frame insertions/deletions and stop-loss variants causing protein length change. This is a missense substitution.
PM5	Not met	PM5 requires a different pathogenic missense change at the same codon. The PM5 candidate search found no pathogenic missense variants at codon 237 (p.Ala237) of CHEK1 in ClinVar or the literature.	pm5_candidates
PM6	Not met	PM6 requires a de novo observation without confirmed maternity and paternity. No de novo observations of NM_001274.5:c.709G>T have been reported.
PP1	Not met	PP1 requires cosegregation with disease in multiple affected family members. No family segregation data are available for this variant.
PP2	Not met	PP2 requires a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. In CHEK1, the established germline disease mechanism is loss-of-function via truncating variants (e.g., c.613+2T>C splice variant causing kinase domain truncation; PMID:38686193), not missense alterations. No missense constraint data (Z-score) support low benign missense variation for CHEK1.
PP3	Not met	PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.067 (strongly predictive of benign), BayesDel score is -0.406 (predictive of benign), and SpliceAI max delta is 0.02 (no predicted splice impact). All available in silico predictors uniformly suggest a benign effect; none support a deleterious impact.	revel bayesdel spliceai
PP4	Not met	PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology. No proband phenotype or family history data are available for this case.
PP5	Not met	PP5 requires a reputable source to have classified the variant as pathogenic. NM_001274.5:c.709G>T is absent from ClinVar. No expert panel or clinical laboratory has reported this variant.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in population databases. The maximum observed frequency is 6.27e-7 (0.00006%) in gnomAD v4.1, far below the 1% threshold.	gnomad_v4
BS1	Not met	BS1 requires an allele frequency >0.3% in population databases (non-VCEP cutoff). The maximum observed frequency is 6.27e-7 (0.00006%) in gnomAD v4.1, far below the 0.3% threshold.	gnomad_v4
BS2	Not met	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). Zero homozygotes are observed in gnomAD, and the single heterozygous carrier does not meet the threshold for BS2.	gnomad_v4
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing. No functional studies have been performed on NM_001274.5:c.709G>T. In silico predictions alone do not satisfy BS3.
BS4	Not met	BS4 requires lack of cosegregation with disease in affected family members. No segregation data are available for this variant.
BP1	Met	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.	pvs1_gene_context
BP2	Not met	BP2 requires observation in trans with a pathogenic dominant variant or in cis with a pathogenic recessive variant. No phase data are available for NM_001274.5:c.709G>T.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. This is a substitution variant.
BP4	Met	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 bayesdel spliceai
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available for this variant.
BP6	Not met	BP6 requires a reputable source to have classified the variant as benign. NM_001274.5:c.709G>T is absent from ClinVar; no source reports it as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_001274.5:c.709G>T is a missense variant (p.Ala237Ser), not synonymous.

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