NM_007194.3:c.715G>A

CHEK2 · NP_009125.1:p.(Glu239Lys) · NM_007194.3

GRCh37: chr22:29107974 C>T · GRCh38: chr22:28711986 C>T

Gene: CHEK2 Transcript: NM_007194.3

Final call

VUS

PM2 moderate

Variant details

Gene

CHEK2

Transcript

NM_007194.3

Protein

NP_009125.1:p.(Glu239Lys)

gnomAD AF

0.0001090526054898073 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The CHEK2 c.715G>A (p.Glu239Lys, p.E239K) variant has been reported in ClinVar with predominantly uncertain significance submissions and one likely pathogenic submission.

This variant is present in gnomAD at 0.00849% in v2.1 and 0.01091% in v4.1, with a highest observed subpopulation frequency of 0.03333%, which is below the 0.1% rarity threshold and does not reach BS1 or BA1 population thresholds.

In a published yeast-based DNA-damage response assay, p.E239K had an intermediate score of 0.58 relative to 1.00 for wild type and 0.00 for a kinase-dead control, which is consistent with partial functional impairment but does not by itself establish a definitive functional criterion strength.

Computational evidence is mixed: SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is 0.445, and BayesDel is 0.263648, so in silico evidence alone does not clearly support either a damaging or benign computational criterion.

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	N/A	This variant is a missense change, not a predicted null variant. Available gene-level context supports CHEK2 loss of function as a disease mechanism, but this specific c.715G>A (p.Glu239Lys, p.E239K) change does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1/2 splice variants.	pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No reviewed evidence was identified showing a different nucleotide change that produces the same amino acid substitution with an established pathogenic classification, so PS1 was not applied.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.
PS3	Not assessed	In a published yeast-based DNA-damage response assay, p.E239K showed an intermediate functional score of 0.58 relative to 1.00 for wild type and 0.00 for a kinase-dead control, suggesting partial loss of function. However, the available evidence does not define a validated criterion strength for applying PS3 to this result alone.	PMID:22419737
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control enrichment data, odds ratio, or multiple well-documented affected observations sufficient for PS4 were identified.	clinvar
PM1	Not met	The variant is located in the CHEK2 kinase domain, but available evidence does not show that residue E239 is in a mutational hotspot or a well-established critical region without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue.	hotspots PMID:22419737
PM2	Met	This variant is present at low frequency in population databases. In gnomAD v2.1 the total allele frequency is 0.00849% (24/282754), and in gnomAD v4.1 it is 0.01091% (176/1613900); the highest observed subpopulation frequency is 0.03333% in Admixed American, which is below the 0.1% rarity threshold.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is intended for recessive disorders with trans observations, which is not the relevant disease mechanism for CHEK2-related cancer predisposition in this case.	cspec
PM4	N/A	This variant is a missense substitution and does not produce a protein length change, so PM4 does not apply.
PM5	N/A	Available review materials did not confirm that classic same-residue PM5 logic should be applied for this case, and no validated same-residue pathogenic comparator was established. PM5 was therefore not applied.	pm5_candidates
PM6	Not assessed	No presumed de novo occurrence without parental confirmation was identified for this variant.
PP1	Not assessed	No segregation data were identified showing that this variant tracks with disease in affected relatives.
PP2	Not assessed	Available evidence does not establish that CHEK2 is a gene in which missense variation is a sufficiently predominant mechanism with a low rate of benign missense variation to support PP2 for this variant.
PP3	Not met	Computational evidence is mixed rather than consistently damaging. SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is 0.445, and BayesDel is 0.263648, so the in silico data do not clearly support a damaging computational criterion.	spliceai revel bayesdel
PP4	Not assessed	No phenotype or family history data specific enough to support a highly specific CHEK2-related clinical presentation were identified for this variant.
PP5	N/A	PP5 is not applied because assertion-only classifications without independently reviewable evidence are not used for this interpretation.
BA1	Not met	Population frequency does not reach a stand-alone benign threshold. The highest observed population frequency is 0.03333% in gnomAD v4.1 Admixed American, which is far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Population frequency is below a benign strong threshold. The highest observed population frequency is 0.03333% in gnomAD v4.1 Admixed American, which is below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not met	This variant has not been observed in the homozygous state in gnomAD, and no evidence was identified showing occurrence in a number of unaffected individuals sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Available functional evidence does not show normal protein function. The published yeast-based DNA-damage response assay gave an intermediate score of 0.58 rather than a wild-type-like result, so BS3 is not supported.	PMID:22419737
BS4	Not assessed	No non-segregation data were identified showing that this variant fails to track with disease in a family.
BP1	Not assessed	Although CHEK2 loss-of-function variants are an established disease mechanism, available evidence does not justify using BP1 to discount this missense variant because damaging CHEK2 missense variants have also been reported.	pvs1_gene_context PMID:22419737
BP2	Not assessed	No phase or co-occurrence data with another pathogenic variant were identified for this case.
BP3	Not assessed	No evidence was identified that this variant is located in a repetitive region or other low-complexity region where in-frame variation is commonly benign.
BP4	Not met	Computational evidence does not consistently support a benign effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but REVEL is 0.445 and BayesDel is 0.263648, so the overall predictor profile is not clearly benign.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular explanation was identified that would account for the disease presentation independently of this variant.
BP6	N/A	BP6 is not applied because assertion-only benign classifications without independently reviewable evidence are not used for this interpretation.
BP7	N/A	This variant is a missense substitution rather than a synonymous or intronic variant, so BP7 does not apply.

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