Variant classification summary

NM_007194.4:c.1095+19G>A

CHEK2 · NP_009125.1:p.? · NM_007194.4

GRCh37: chr22:29092870 C>T · GRCh38: chr22:28696882 C>T

Gene: CHEK2 Transcript: NM_007194.4

Final call

Likely Benign

BS2 supporting BP4 supporting BP6 supporting

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.?

gnomAD AF

0.00012058471919319746 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007194.4:c.1095+19G>A is an intronic variant in CHEK2 located at position +19 in intron 10.

2

Computational evidence predicts no splicing impact: SpliceAI maximum delta score is 0.00 across all categories, consistent with a neutral intronic change (BP4_Supporting).

3

A homozygous individual for this variant is observed in gnomAD v4.1, which is inconsistent with a highly penetrant autosomal dominant cancer predisposition variant (BS2_Supporting).

4

ClinVar reports this variant as Likely benign by 9 clinical laboratories and Benign by 3 clinical laboratories (Variation ID: 371849), providing reputable source support for a benign interpretation (BP6_Supporting).

5

The variant is observed at population frequencies of 0.017% (gnomAD v2.1) and 0.012% (gnomAD v4.1) with the highest subpopulation frequency of 0.237% in the Middle Eastern population (gnomAD v4.1), which approaches but does not exceed the BS1 threshold of 0.3%.

6

No functional studies, segregation data, case-control enrichment, or variant-specific publications were identified for this variant.

7

Three benign supporting criteria (BP4, BP6, BS2) are met. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), two or more benign supporting criteria support a Likely Benign classification.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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.1095+19G>A is an intronic variant located 19 bases downstream of exon 10, outside the canonical ±1,2 splice donor/acceptor consensus. It does not fall into the null-variant buckets of nonsense, frameshift, or canonical splice consensus required for PVS1 application. The generic PVS1 decision framework confirms apply_generic_pvs1_framework=false.	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 requires a different nucleotide change at the same position that has been established as pathogenic. No known pathogenic variant exists at the c.1095+19 position in CHEK2.
PS2	Not met	No de novo data are available for NM_007194.4:c.1095+19G>A. No publications or ClinVar submissions report de novo occurrence of this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies are available for NM_007194.4:c.1095+19G>A. No publications reporting functional characterization of this variant were identified.
PS4	Not met	No case-control enrichment data are available for NM_007194.4:c.1095+19G>A. The variant is observed in 47/282,086 alleles in gnomAD v2.1 and 186/1,542,484 alleles in gnomAD v4.1, consistent with a benign polymorphism rather than enriched in affected individuals.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a criterion in the generic ACMG/AMP 2015 framework (PMID:25741868). The standard pathogenic criteria extend from PVS1 through PP5. No gene-specific VCEP/CSPEC framework defines a PS5 criterion for CHEK2.
PM1	Not met	NM_007194.4:c.1095+19G>A is a deep intronic variant located 19 bases downstream of exon 10. It does not reside in a mutational hotspot or well-established critical functional domain. No OncoKB hotspot data support pathogenic clustering at this position.
PM2	Not met	PM2 requires absence or extremely low frequency in population databases. NM_007194.4:c.1095+19G>A is present in gnomAD v2.1 at AF=0.017% (47/282,086 alleles) and in gnomAD v4.1 at AF=0.012% (186/1,542,484 alleles, including 1 homozygote). While below the 0.1% threshold, the presence of a homozygous individual in an autosomal dominant cancer predisposition gene and frequencies exceeding those expected for a highly penetrant pathogenic variant argue against PM2 application.	gnomad_v2 gnomad_v4
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; PM3 is not applicable.
PM4	N/A	PM4 applies to protein length changes from non-frameshift indels, stop-loss, or initiation codon variants. NM_007194.4:c.1095+19G>A is a single nucleotide intronic substitution, not a protein-length altering change.
PM5	N/A	PM5 applies to novel missense variants occurring at the same amino acid residue as a known pathogenic missense variant. NM_007194.4:c.1095+19G>A is an intronic variant with no protein consequence (NP_009125.1:p.?); no amino acid residue can be assigned, making PM5 inapplicable.
PM6	Not met	No de novo data are available for NM_007194.4:c.1095+19G>A. No publications or ClinVar submissions report de novo occurrence with confirmed maternity and paternity.
PP1	Not assessed	No cosegregation data are available for NM_007194.4:c.1095+19G>A. No family studies or linkage data have been reported.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_007194.4:c.1095+19G>A is an intronic variant, not a missense change.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta score = 0.00 for all categories: acceptor gain, acceptor loss, donor gain, donor loss). REVEL and BayesDel scores are not available for this intronic variant as they require missense changes. No in silico tool predicts pathogenicity.	spliceai
PP4	Not assessed	No patient phenotype or family history data are available for independent assessment. This adjudication is performed without access to the proband's clinical presentation or family history.
PP5	Not met	PP5 requires a reputable source to have recently reported the variant as pathogenic. ClinVar classification for this variant is Likely benign (9 clinical laboratories) and Benign (3 clinical laboratories). No reputable source reports this variant as pathogenic.	clinvar
BA1	Not met	BA1 requires allele frequency >1% in population databases. The highest observed population frequency is 0.237% in the Middle Eastern subpopulation (gnomAD v4.1) and 0.095% in the South Asian subpopulation (gnomAD v2.1). Neither approaches the 1% stand-alone benign threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires allele frequency greater than expected for disorder (>0.3% by non-VCEP threshold). The highest observed population frequency is 0.237% in the Middle Eastern subpopulation (gnomAD v4.1), which approaches but does not exceed the 0.3% threshold. The overall AF across all populations is 0.012–0.017%.	gnomad_v2 gnomad_v4
BS2	Met	A homozygous individual for NM_007194.4:c.1095+19G>A is observed in gnomAD v4.1 (1 homozygote among 1,542,484 alleles). CHEK2 is an autosomal dominant cancer predisposition gene where biallelic pathogenic variants would be expected to cause a severe or embryonic lethal phenotype. Observation of a homozygote in a population database is inconsistent with a highly penetrant pathogenic role and supports a benign interpretation.	gnomad_v4
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for NM_007194.4:c.1095+19G>A. While SpliceAI predicts no splice impact (computational, not functional), no experimental studies such as minigene splicing assays or RT-PCR have been performed for this variant.
BS4	Not assessed	No segregation data are available to assess lack of cosegregation with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_007194.4:c.1095+19G>A is an intronic variant, not a missense change.
BP2	Not assessed	No phasing data are available to assess whether this variant has been observed in trans with a pathogenic CHEK2 variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. NM_007194.4:c.1095+19G>A is a single nucleotide intronic substitution, not an in-frame indel.
BP4	Met	Computational evidence suggests no impact on splicing. SpliceAI predicts no splice alteration with a maximum delta score of 0.00 across all categories (acceptor gain, acceptor loss, donor gain, donor loss). The variant resides at position +19 in intron 10, well outside the canonical splice consensus, consistent with a neutral intronic change.	spliceai
BP5	Not assessed	No data are available indicating an alternate molecular basis for disease in a case carrying this variant.
BP6	Met	ClinVar reports NM_007194.4:c.1095+19G>A as Likely benign by 9 clinical laboratories and Benign by 3 clinical laboratories (Variation ID: 371849). Multiple independent clinical laboratories have reached a benign or likely benign classification, providing reputable source support for a benign interpretation.	clinvar
BP7	N/A	BP7 is defined for synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_007194.4:c.1095+19G>A is an intronic variant, not a synonymous coding change. BP7 does not apply.

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