Variant classification summary

NM_007194.4:c.1513T>A

CHEK2 · NP_009125.1:p.(Ser505Thr) · NM_007194.4

GRCh37: chr22:29085152 A>T · GRCh38: chr22:28689164 A>T

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Ser505Thr)

gnomAD AF

2.757967077394824e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007194.4:c.1513T>A (p.Ser505Thr) is a missense variant in exon 14 of CHEK2, a gene associated with autosomal dominant hereditary breast, ovarian, pancreatic, and prostate cancer predisposition.

2

This variant is present at very low frequency in gnomAD: 17/233,642 alleles in v2.1 (AF=0.00728%) and 44/1,595,378 alleles in v4.1 (AF=0.00276%), with the highest subpopulation frequency of 0.083% in East Asians, all below the 0.1% PM2 threshold (PM2_Supporting).

3

Multiple in silico tools unanimously predict a benign effect: REVEL score 0.018 (benign range), BayesDel score -0.428 (benign range), and SpliceAI max delta 0.00 (no predicted splice impact) (BP4_Supporting).

4

PVS1 is not applicable as this is a missense variant, not a null variant. PS1 and PM5 are not applicable as no same-residue pathogenic comparators have been identified. BP7 is not applicable as the variant is not synonymous.

5

ClinVar consensus is Likely benign from four clinical laboratories, with one additional submitter reporting Uncertain significance and one reporting likely benign. No expert panel classification is available, and no reputable source has classified this variant as pathogenic.

6

Functional evidence (PS3/BS3) remains unassessed pending full-text review of PMID:30851065 (Delimitsou et al. 2019), which performed functional characterization of CHEK2 variants in a yeast system and may include p.Ser505Thr.

7

No de novo reports (PS2/PM6), no case-control enrichment data (PS4), no co-segregation data (PP1), and no trans-observation with a pathogenic variant (BP2) are available for this variant.

8

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868) with PM2_Supporting (1 pathogenic point) and BP4_Supporting (1 benign point), the variant is classified as a Variant of Uncertain Significance (VUS), with the benign and pathogenic evidence effectively balancing each other. The CSPEC CHEK2 VCEP v1.0.0 (doc 522546466) did not provide machine-interpretable criteria beyond the raw ruleset.

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	NM_007194.4:c.1513T>A is a missense variant (p.Ser505Thr) in exon 14 of CHEK2, not a null variant (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon loss, or exon deletion). PVS1 is not applicable to missense variants.	pvs1_generic_framework
PS1	N/A	No previously classified pathogenic variant with the exact same amino acid change (p.Ser505Thr) at this residue has been identified in ClinVar or the literature.
PS2	Not met	No confirmed de novo occurrence of NM_007194.4:c.1513T>A has been reported in published literature or databases.
PS3	Not assessed	Functional data for NM_007194.4:c.1513T>A (p.Ser505Thr) could not be confirmed. PMID:30851065 (Delimitsou et al. 2019, functional characterization of CHEK2 variants in yeast) may contain functional assessment of this variant, but full-text verification is unavailable in the case directory. OncoKB reports no variant-specific reviewed functional evidence.	PMID:30851065
PS4	Not met	No case-control study or statistical enrichment analysis specifically reporting an odds ratio for NM_007194.4:c.1513T>A in CHEK2-associated cancers (breast, ovarian, pancreatic, prostate) has been identified. gnomAD allele frequencies are low but do not by themselves establish case enrichment.	gnomad_v2 gnomad_v4
PS5	N/A	No previously classified pathogenic variant with a different amino acid change at residue 505 has been identified. PM5 candidate assessment confirmed no same-residue comparators.
PM1	Not assessed	Residue Ser505 lies within the CHEK2 protein kinase domain (approximately residues 220-540). However, the CHEK2 VCEP v1.0.0 does not provide machine-readable domain-level PM1 specifications for critical functional domains, and gnomAD shows a subpopulation frequency of 0.083% in East Asians (v2.1), indicating some population tolerance for missense variation in this region. Without explicit VCEP-defined critical domain boundaries and benign-variation-free thresholds, PM1 cannot be cleanly applied under the current framework.	gnomad_v2 cspec
PM2	Met	NM_007194.4:c.1513T>A is present at very low frequency in general population databases. gnomAD v2.1: 17/233,642 alleles (AF=0.00728%). gnomAD v4.1: 44/1,595,378 alleles (AF=0.00276%). The highest subpopulation frequency is in East Asians at 0.083% (v2.1, 15/17,996) and 0.078% (v4.1, 35/44,872), both below the 0.1% PM2 threshold for a gene with CHEK2-associated cancer predisposition. No homozygotes observed. Absent from gnomAD-Canada.	gnomad_v2 gnomad_v4
PM5	N/A	No pathogenic variant at the same residue (Ser505) with a different amino acid substitution has been identified in ClinVar or literature. PM5 candidate harvesting returned zero candidates at this codon.
PM6	Not met	No evidence for assumed de novo occurrence (i.e., de novo without confirmed paternity/maternity) has been identified for this variant in published literature or databases.
PP1	Not met	No co-segregation data with disease in multiple affected family members has been reported for NM_007194.4:c.1513T>A.
PP2	N/A	PP2 applies to genes where missense variants are a common mechanism of disease and benign missense variation is rare. CHEK2 has numerous missense variants in gnomAD with measurable population frequencies, and pathogenic CHEK2 variants include both truncating and missense types. PP2 is not appropriate for CHEK2 under generic ACMG/AMP guidelines.	gnomad_v2 gnomad_v4
PP3	Not met	Multiple in silico prediction tools uniformly predict a benign impact for p.Ser505Thr. REVEL score is 0.018 (well below the pathogenic threshold of ~0.5, firmly in benign range). BayesDel score is -0.428 (benign range, below pathogenic threshold). SpliceAI delta score is 0.00 (no predicted splice alteration). No computational evidence supports a deleterious effect.	revel bayesdel spliceai
PP4	Not met	Insufficient clinical data demonstrating that the variant-carrier phenotype or family history is highly specific for CHEK2-associated disease. No detailed clinical case descriptions identifying this variant in patients with CHEK2-specific tumor spectrum and family history are available.
PP5	Not met	No reputable source (e.g., expert panel, clinical guideline) has classified NM_007194.4:c.1513T>A as pathogenic or likely pathogenic. ClinVar consensus is Likely benign from multiple clinical laboratories. The ClinGen CHEK2 VCEP has not issued a classification for this variant.	clinvar
BA1	Not met	The maximum population minor allele frequency for NM_007194.4:c.1513T>A is 0.083% in East Asians (gnomAD v2.1) and 0.078% in East Asians (gnomAD v4.1), both well below the 1% BA1 threshold. The variant is not common enough to meet BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum population allele frequency of 0.083% in East Asians (gnomAD v2.1) is below the 0.3% BS1 threshold. The variant is not sufficiently common in control populations to meet BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of NM_007194.4:c.1513T>A in a homozygous state in gnomAD (0 homozygotes across v2.1 and v4.1) nor reported in trans with a known pathogenic CHEK2 variant in a healthy adult. Insufficient evidence to satisfy BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Normal functional evidence for NM_007194.4:c.1513T>A (p.Ser505Thr) could not be confirmed. No variant-specific benign functional data was identified in OncoKB. PMID:30851065 (Delimitsou et al. 2019) performed functional characterization of CHEK2 variants in a yeast system but full-text is unavailable for confirmation of whether p.Ser505Thr was included and showed wild-type-like function.	PMID:30851065
BS4	Not met	No co-segregation or family data are available demonstrating lack of segregation of NM_007194.4:c.1513T>A with disease in affected families.
BP1	Not met	BP1 is applicable to missense variants in genes where primarily truncating variants are known to cause disease. While CHEK2 has well-established pathogenic truncating variants (e.g., 1100delC), it also has recognized pathogenic missense variants. Therefore, BP1 does not apply.
BP2	Not met	No observation of NM_007194.4:c.1513T>A in trans with a known pathogenic CHEK2 variant has been reported in the literature or databases.
BP4	Met	Multiple lines of computational evidence unanimously predict no damaging effect for p.Ser505Thr. REVEL score is 0.018 (benign range), BayesDel score is -0.428 (benign range), and SpliceAI predicts no splice alteration (max delta = 0.00). These complementary in silico tools provide consistent evidence that the missense substitution is tolerated at the protein level.	revel bayesdel spliceai
BP5	Not met	No case has been identified where NM_007194.4:c.1513T>A is observed in an individual with an alternate molecular basis for disease. There is no evidence to support BP5.
BP6	Not met	No expert panel or other highly reputable source has classified NM_007194.4:c.1513T>A as benign. While multiple clinical laboratories have classified this variant as Likely benign in ClinVar, the review status is 'criteria provided, single submitter' without expert panel consensus. BP6 requires a reputable source reporting the variant as benign with evidence unavailable for independent evaluation; Likely benign from individual clinical laboratories does not meet this threshold.	clinvar
BP7	N/A	NM_007194.4:c.1513T>A is a missense variant (p.Ser505Thr), not a synonymous/silent variant. BP7 applies only to synonymous variants with no predicted splice impact.

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