Variant classification summary

NM_007194.4:c.1100del

CHEK2 · NP_009125.1:p.(Thr367MetfsTer15) · NM_007194.4

GRCh37: chr22:29091856 AG>A · GRCh38: chr22:28695868 AG>A

Gene: CHEK2 Transcript: NM_007194.4

Final call

Pathogenic

PVS1 very strong PS3 supporting PS4 strong PP1 supporting

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Thr367MetfsTer15)

gnomAD AF

0.0021516173435128147 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong reflects a premature truncation in exon 11 of 14 in LOF-dependent CHEK2.

2

Pathogenic: PS3 supporting reflects reported loss of CHEK2 kinase activity for the exact allele.

3

Pathogenic: PS4 strong reflects exact-variant enrichment with OR 13.84 and 95% CI 5.51-34.81.

4

Pathogenic: PP1 supporting reflects carriage in 16 of 27 additional affected relatives.

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong pathogenic criterion plus one strong pathogenic criterion satisfies the Pathogenic combination rule; additional supporting criteria do not alter the call.

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	Met	Met at very strong: c.1100del causes p.Thr367MetfsTer15 in exon 11 of 14, a premature truncation expected to undergo NMD in LOF-dependent CHEK2.	pvs1_variant_assessment pvs1_generic_framework PMID:11967536
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented de novo occurrence with both maternity and paternity confirmed and no family history.	PMID:11967536
PS3	Met	Met at supporting strength: the exact CHEK2*1100delC allele was reported to abrogate CHEK2 kinase activity, but clinical-laboratory validation and independent replication are not documented.	PMID:11967536
PS4	Met	Met: exact-variant case-control enrichment in male-breast-cancer families produced OR 13.84 (95% CI 5.51-34.81), exceeding the PS4 threshold of >5.0 with CI excluding 1.0.	PMID:11967536 PMID:28779002
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM2	Not met	Not met: non-cancer gnomAD v2.1 exomes show AF 0.00205, exceeding the generic PM2 supporting threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: CHEK2-related cancer predisposition is autosomal dominant, whereas PM3 is restricted to recessive disorders.	cspec
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no reported assumed de novo occurrence exists, even without parental confirmation.	PMID:11967536
PP1	Met	Met at supporting strength: 16 of 27 additional affected relatives carried the variant versus 41% expected without association.	PMID:11967536
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: c.1100del is a frameshift variant, whereas generic PP3 applies only to missense or intronic/splice-region variants.
PP4	Not assessed	Not assessed: no individual phenotype or sufficiently specific family history is available to evaluate the PP4 requirement for a single genetic etiology.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel classification, so ordinary laboratory and aggregate Pathogenic labels cannot trigger PP5.	clinvar
BA1	Not met	Not met: the highest observed frequency is 0.872% in Finnish non-cancer exomes, below the 5% BA1 stand-alone threshold.	gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: overall AF is 0.205%, but reduced penetrance and founder enrichment require a disorder-specific maximum-credible-frequency calculation beyond the 1% default.	gnomad_v2 gnomad_v4 PMID:11967536
BS2	N/A	Not applicable: CHEK2 c.1100delC is reduced-penetrance and later-onset, contrary to the BS2 requirement for full early-age penetrance.	gnomad_v2 gnomad_v4 PMID:11967536
BS3	Not assessed	Not assessed: no evidence shows that CHEK2 c.1100del has no damaging effect on protein function or splicing.
BS4	Not assessed	Not assessed: the available family data show 16 of 27 affected relatives carrying the variant, not documented lack of segregation.	PMID:11967536
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no documented cis phase with a pathogenic variant, and the evidence does not establish a fully penetrant dominant disorder for BP2's trans path.	cspec PMID:11967536
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: c.1100del is a frameshift, and SpliceAI max delta 0.013 cannot support BP4 by negating its truncating protein effect.
BP5	Not assessed	Not assessed: no individual case is documented with an alternate molecular basis for the disease.
BP6	Not met	Not met: the exact variant lacks an expert-panel Benign or Likely benign classification; the available ClinVar record is Pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a frameshift variant.	generic_acmg_combination_rules

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