NM_007194.4:c.751A>T

CHEK2 · NP_009125.1:p.(Ile251Phe) · NM_007194.4

GRCh37: chr22:29107938 T>A · GRCh38: chr22:28711950 T>A

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PM1 moderate PM2 supporting BS4 supporting benign

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Ile251Phe)

gnomAD AF

3.2839176021701116e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM1 (moderate) is met: the variant alters Ile251 in the CHEK2 kinase domain, a well-established critical functional domain.

PM2 (supporting) is met: the variant is present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00177%, gnomAD v4.1 AF=0.00328%).

BS4 (supporting benign) is met: the variant demonstrated lack of segregation in a familial prostate cancer family, where it was detected in only 1 of 2 affected brothers.

The variant has been observed in individual cases of familial prostate cancer (1/298) and hereditary breast cancer (1/507) but has not demonstrated statistically significant case-control enrichment.

No variant-specific functional studies have been performed for p.Ile251Phe. In silico predictions are mixed: REVEL=0.426, BayesDel=0.178, PolyPhen-2=Probably damaging, SIFT=Tolerated.

ClinVar classification is Uncertain significance (15 VUS, 3 Likely pathogenic submissions). No expert panel review has been performed.

With one moderate pathogenic criterion (PM1), one supporting pathogenic criterion (PM2), and one supporting benign criterion (BS4), the evidence is equivocal and the variant remains a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Not met	This variant is a missense substitution (c.751A>T, p.Ile251Phe) and does not fall into a null-variant category (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion). PVS1 is not applicable to missense variants under generic ACMG/AMP 2015 rules.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence that a different nucleotide change at c.751 resulting in the same amino acid alteration (p.Ile251Phe) has been established as pathogenic.
PS2	Not met	No de novo observation has been reported for this variant.
PS3	Not met	No variant-specific functional assay has been performed for p.Ile251Phe. The kinase activity assay in Desrichard et al. (PMID:22114986) tested 11 CHEK2 missense variants but did not include p.Ile251Phe. Dong et al. (PMID:12533788) performed western blot analysis for frameshift mutations only; missense variants were used as controls showing normal protein levels but p.Ile251Phe was not individually characterized.	PMID:12533788 PMID:22114986
PS4	Not met	The variant has been observed in individual cases across two studies (1/298 familial prostate cancer in Dong et al. 2003, 1/507 hereditary breast cancer cases in Desrichard et al. 2011) but has not been subjected to a statistical case-control analysis demonstrating significant enrichment over population controls. Individual case observations do not meet the threshold for PS4.	PMID:12533788 PMID:22114986 PMID:28135145
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion and no VCEP-specific PS5 rule has been defined for CHEK2.
PM1	Met	The variant alters residue Ile251 in the CHEK2 kinase domain (residues ~220–500), a well-established critical functional domain essential for CHEK2 kinase activity and DNA damage signaling. Missense substitutions in the kinase domain have been shown to abolish CHEK2 function.	PMID:12533788 PMID:22114986
PM2	Met	The variant is present at an extremely low frequency in population databases: gnomAD v2.1 AF=0.00177% (5/282,756 alleles), gnomAD v4.1 AF=0.00328% (53/1,613,926 alleles), and absent from gnomAD-Canada. These frequencies are well below the PM2 threshold of 0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. CHEK2-related cancer predisposition is autosomal dominant.
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. This is a missense substitution.
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Ile251) has been identified in ClinVar or the literature. The automated PM5 candidate search did not yield any same-residue comparator variants.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant. PM6 requires a de novo observation with confirmed maternity and paternity.
PP1	Not met	In the familial prostate cancer family reported by Dong et al. (PMID:12533788), the A751T variant was detected in only 1 of 2 affected brothers tested, demonstrating lack of co-segregation with disease in the family.	PMID:12533788
PP2	Not met	Gene-level missense constraint data are not available to confirm that CHEK2 has a low rate of benign missense variation. CHEK2 has multiple reported pathogenic missense variants (e.g., p.Ile157Thr, p.Arg145Trp, p.Arg117Gly), which argues against a gene-wide application of PP2.
PP3	Not met	Computational evidence is mixed and does not meet the threshold for multiple lines supporting a deleterious effect. REVEL score is 0.426 (below 0.5 threshold), BayesDel score is 0.178 (below deleterious threshold), and SpliceAI predicts no splicing impact (max delta=0.00). PolyPhen-2 predicted 'Probably damaging' in Desrichard et al. (PMID:22114986), but Align-GVGD class C0 and SIFT predicted 'Tolerated.' The preponderance of in silico tools does not converge on a deleterious prediction.	revel bayesdel spliceai PMID:22114986
PP4	Not met	The variant has been observed in patients with prostate cancer, breast cancer, and colorectal cancer — phenotypes that are not highly specific for a single genetic etiology. CHEK2-related cancer predisposition has a broad and overlapping phenotype spectrum that does not satisfy PP4's requirement for a highly specific phenotype.
PP5	Not met	The variant is classified as 'Uncertain significance' overall in ClinVar (ClinVarID 128086). While 3 of 20 submissions classified it as 'Likely pathogenic,' the majority (15 submissions) classified it as VUS. No expert panel has reviewed this variant. PP5 requires a reputable source reporting the variant as pathogenic, which is not met by the current ClinVar consensus.	clinvar
BA1	Not met	The maximum population allele frequency is 0.00387% (gnomAD v2.1, European non-Finnish), far below the BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	The population allele frequency (gnomAD v2.1 AF=0.00177%, gnomAD v4.1 AF=0.00328%) is well below the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals have been observed, and there are no confirmed observations of this variant in healthy adult individuals with documented normal phenotype to satisfy BS2.
BS3	Not met	No variant-specific functional assay demonstrating a benign effect has been performed for p.Ile251Phe. The kinase assay in Desrichard et al. did not include this variant. Dong et al. showed normal CHEK2 protein levels for pooled missense variants by western blot, but p.Ile251Phe was not individually characterized. This does not constitute well-established functional evidence of no damaging effect.	PMID:12533788 PMID:22114986
BS4	Met	In the familial prostate cancer family reported by Dong et al. (PMID:12533788), the c.751A>T variant was detected in only 1 of 2 affected brothers, demonstrating lack of segregation with disease. This represents a non-segregation event in affected family members supporting a benign interpretation.	PMID:12533788
BP1	Not met	CHEK2 has multiple established pathogenic missense variants (e.g., p.Ile157Thr, p.Arg145Trp, p.Arg117Gly, p.Thr476Met) in addition to truncating variants. BP1 is applicable only to genes where the primary disease mechanism is truncating variants, which is not the case for CHEK2.	PMID:22114986
BP2	Not met	No evidence of this variant being observed in trans with a known pathogenic CHEK2 variant, or in cis with a known pathogenic variant in any inheritance pattern.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
BP4	Not met	Computational evidence does not converge on a benign prediction. PolyPhen-2 predicted 'Probably damaging' (PMID:22114986), while REVEL (0.426) and BayesDel (0.178) are in the indeterminate range. SpliceAI predicts no splicing impact. The in silico evidence is mixed and does not meet the 'multiple lines suggesting no impact' threshold for BP4.	revel bayesdel spliceai PMID:22114986
BP5	Not met	No evidence that this variant has been found in a case with an alternate molecular basis for disease. BP5 requires observation in an individual with a confirmed alternate genetic cause for the same phenotype.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar consensus is 'Uncertain significance.' BP6 requires a reputable source reporting the variant as benign with unavailable evidence.	clinvar
BP7	N/A	This is a missense variant (c.751A>T, p.Ile251Phe). BP7 applies only to synonymous (silent) variants with no predicted splicing impact.

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