Variant classification summary

NM_007194.4:c.1312G>T

CHEK2 · NP_009125.1:p.(Asp438Tyr) · NM_007194.4

GRCh37: chr22:29091178 C>A · GRCh38: chr22:28695190 C>A

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PS3 supporting PM1 moderate BP4 supporting

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Asp438Tyr)

gnomAD AF

0.00037558150056585135 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

This variant is located in the kinase domain of CHEK2, a critical functional domain where pathogenic missense variants are known to cluster.

2

The variant was directly studied in at least one publication (Baloch et al.) examining CHEK2 missense mutations and breast cancer risk, but functional assay results are conflicting across studies — some report reduced kinase activity while others show wild-type-like function.

3

The variant is present in gnomAD v4.1 at an allele frequency of 0.038% (606 alleles, including 3 homozygotes), which exceeds the PM2 threshold of <0.1% and is notable but below BS1 threshold of >0.3%.

4

In silico tools do not support a pathogenic role: REVEL score 0.337, BayesDel score -0.013, and SpliceAI max delta 0.05 all indicate a likely benign or indeterminate effect.

5

ClinVar classification is conflicted between Uncertain significance (19 clinical laboratories) and Likely benign (13 clinical laboratories), with overall review status of criteria provided, single submitter (1-star).

6

One ClinVar submitter reports non-segregation of this variant with disease in a family and observation in unaffected controls, but the primary literature could not be verified.

7

Overall, pathogenic evidence (PM1_moderate, PS3_supporting) is balanced by benign evidence (BP4_supporting), resulting in a classification of Uncertain Significance.

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	Missense variant (c.1312G>T, p.Asp438Tyr); does not meet PVS1 null-variant criteria of nonsense, frameshift, or canonical splice ±1,2 consensus variants.	pvs1_generic_framework
PS1	N/A	No different nucleotide change at the same amino acid position with established pathogenicity is known.
PS2	Not assessed	No de novo data available for this variant.
PS3	Met	The variant p.Asp438Tyr was directly studied in PMID:24390236 (title: 'Missense mutations (p.H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin'). Multiple ClinVar submitters reference functional kinase activity assays for this variant (referenced as Baloch 2014 and Bell 2007), reporting intermediate to reduced kinase activity in some studies but conflicting results across laboratories. Full text of PMID:24390236 and PMID:18571837 were not available in the case folder for independent verification of functional assay details. Supporting strength assigned because the variant was directly studied but functional data are conflicting and no systematic range characterization (tiling/saturation mutagenesis) is documented.	PMID:24390236 PMID:18571837 clinvar
PS4	Not assessed	Multiple cohort studies are referenced in ClinVar submissions (PMIDs: 25186627, 27443514, 29484706, 29987844, 36260514, 37656691) but variant-specific case-control or enrichment data could not be independently verified from available abstracts. The ClinVar LabCorp submission additionally notes the variant was observed in unaffected controls.
PS5	N/A	No de novo observation reported for this variant.
PM1	Met	Variant p.Asp438Tyr is located in the serine/threonine kinase domain of CHEK2 (residues ~220-486), a well-established critical functional domain where pathogenic missense variants cluster. The kinase domain is required for CHEK2 checkpoint function, and missense alterations in this domain are a recognized mechanism of CHEK2-related cancer predisposition.	PMID:24390236 PMID:18571837
PM2	Not met	This variant is present in gnomAD v4.1 at an allele frequency of 0.03756% (606/1,613,498 alleles, including 3 homozygotes) with grpmax FAF of 0.23% in the Amish population. This exceeds the PM2 threshold of <0.1% allele frequency in population databases. gnomAD v2.1 similarly shows AF 0.03859% (109/282,442 alleles).	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue pathogenic comparator variants with a different amino acid change were identified.
PM6	Not assessed	No de novo data available for this variant.
PP1	Not assessed	Segregation data referenced in ClinVar submissions: the LabCorp submission (SCV000698770) reports that this variant did not segregate with disease in at least one family and was also observed in unaffected controls. However, the primary literature supporting these claims (referenced as 'baloch_2') is not available for independent verification.	clinvar
PP2	N/A	CHEK2 is not a gene where missense variants are the predominant pathogenic mechanism; both truncating and missense variants are established as disease-associated. PP2 applies only when missense is the primary mechanism and benign missense variation is rare.
PP3	Not met	In silico tools do not consistently predict a damaging effect. REVEL score is 0.337 (below the commonly accepted pathogenicity threshold of 0.5), BayesDel score is -0.013 (predicts benign), and SpliceAI max delta is 0.05 (no predicted splicing impact). While one ClinVar submitter reported 4 of 5 in silico tools predicted damaging effect, the quantitative scores available for this adjudication indicate a benign or indeterminate prediction.	revel bayesdel spliceai
PP4	Not assessed	Variant reported in individuals with personal or family history of breast, prostate, or colorectal cancer per ClinVar submissions, but also reported in unaffected controls. Specific patient phenotypes could not be independently verified from available primary literature.	clinvar
PP5	Not met	ClinVar review status is 'criteria provided, single submitter' (1-star). PP5 requires a 3-star expert panel review status or higher. Overall ClinVar classification is conflicting between Uncertain significance (19 submitters) and Likely benign (13 submitters).	clinvar
BA1	Not met	gnomAD v4.1 allele frequency 0.03756% is well below the BA1 threshold of >1%. The highest subpopulation frequency (Amish) is 0.55%, which also falls below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD v4.1 allele frequency 0.03756% and gnomAD v2.1 AF 0.03859% are both below the BS1 threshold of >0.3%. The grpmax FAF of 0.23% in v4.1 (Amish) also falls below the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Observed in 3 homozygous individuals in gnomAD v4.1. However, CHEK2-related cancer predisposition has incomplete penetrance and adult onset; BS2 requires observation in healthy adults for a disorder with full penetrance expected at an early age. The presence of homozygotes is notable but does not satisfy the strict BS2 criteria given the moderate-penetrance, adult-onset nature of CHEK2-associated cancer risk.	gnomad_v4
BS3	Not assessed	Functional studies referenced by ClinVar submitters are conflicting: some studies report reduced kinase activity (~70% decrease per one submitter), while others, including a human cell-based assay, show activity comparable to wild-type. Full texts of the primary functional studies (PMID:24390236, PMID:18571837) were not available for independent assessment of assay methodology and results.	clinvar
BS4	Not assessed	One ClinVar submitter (LabCorp, SCV000698770, classified Likely benign) reports that this variant did not segregate with disease in at least one family and was also observed in unaffected controls. The primary literature supporting this claim is referenced as 'baloch_2' (likely a study of the Balochistan population) but the full text is not available for independent verification of the segregation analysis.	clinvar
BP1	N/A	BP1 applies when a missense variant occurs in a gene where truncating variants are the only known pathogenic mechanism. In CHEK2, both truncating (e.g., c.1100delC) and missense variants are established as pathogenic, so BP1 does not apply.
BP2	N/A	No observation of this variant in trans with a known pathogenic CHEK2 variant. Without such observation, BP2 cannot be applied.
BP4	Met	Multiple in silico tools predict a benign effect for this variant. REVEL score is 0.337 (below the pathogenic threshold of 0.5), BayesDel score is -0.013 (predicts benign), and SpliceAI max delta is 0.05 (no predicted splicing impact). These quantitative, variant-specific scores support a benign interpretation.	revel bayesdel spliceai
BP5	Not assessed	No observation of this variant in an individual with an alternate molecular basis for disease. BP5 requires a case where another pathogenic variant explains the phenotype.
BP6	Not met	ClinVar review status is 'criteria provided, single submitter' (1-star). BP6 requires a 3-star expert panel review or higher with a benign or likely benign classification. The overall ClinVar classification is conflicted between VUS and Likely benign.	clinvar
BP7	N/A	BP7 applies only to synonymous variants with no predicted splicing impact. This is a missense variant (c.1312G>T, p.Asp438Tyr).

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