NM_007194.4:c.-6-8T>G

CHEK2 · NP_009125.1:p.? · NM_007194.4

GRCh37: chr22:29130723 A>C · GRCh38: chr22:28734735 A>C

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.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The CHEK2 NM_007194.4:c.-6-8T>G (NP_009125.1:p.?) variant has been reported in ClinVar as likely benign by a single clinical laboratory.

This variant is absent from gnomAD v2.1 and is present only 3 times in 1,612,954 alleles in gnomAD v4.1 (overall AF 1.85994e-06; highest observed population AF 1.6001e-05), supporting rarity but not a benign frequency threshold.

In silico splicing analysis does not support a meaningful splice effect, with SpliceAI showing a maximum delta score of 0.10.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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 intronic variant is outside the canonical splice ±1,2 positions, and the generic PVS1 assessment concluded that it does not fall into the default null-variant categories used for PVS1. Although loss of function is an established CHEK2 disease mechanism, available evidence does not show that this specific non-canonical intronic change causes loss of function.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	This variant does not have a defined protein consequence, so there is no basis to assess whether it produces the same amino acid change as an established pathogenic variant.
PS2	Not assessed	No confirmed de novo occurrence data were identified for this variant.	clinvar
PS3	Not assessed	No well-established functional study was identified showing that this variant damages CHEK2 function or causes abnormal splicing.	spliceai
PS4	Not met	Available evidence does not show an increased prevalence of this variant in affected individuals compared with controls. Only a single ClinVar submission was identified, which is insufficient for a case-enrichment assertion.	clinvar
PM1	Not met	This variant is located in a non-canonical intronic region rather than a known CHEK2 mutational hotspot or well-established critical functional domain with low benign variation.
PM2	Met	This variant is absent from gnomAD v2.1 and is present only 3 times in 1,612,954 alleles in gnomAD v4.1 (overall AF 1.85994e-06, 0.00019%; highest observed population AF 1.6001e-05, 0.00160%), which is well below a 0.1% rarity threshold and supports rarity.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is intended for recessive disorders with pathogenic variants detected in trans, which is not the relevant inheritance framework for CHEK2-related cancer predisposition.	cspec
PM4	N/A	This intronic variant does not change protein length and is not an in-frame deletion, insertion, or stop-loss variant.
PM5	N/A	This variant does not have a defined missense protein consequence, so there is no basis to compare it with other pathogenic missense changes at the same residue.
PM6	Not assessed	No assumed de novo occurrence without parental confirmation was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	N/A	PP2 is a missense-specific criterion and does not apply to this intronic variant.
PP3	Not met	Available computational evidence does not support a damaging effect on splicing. SpliceAI showed a maximum delta score of 0.10, which does not indicate a significant splice impact.	spliceai
PP4	Not assessed	No phenotype information was provided that would allow assessment of whether the clinical presentation is highly specific for CHEK2-related disease.	cspec
PP5	Not assessed	This criterion was not used because assertion-based evidence without accessible supporting data is not considered sufficient for independent classification.	clinvar
BA1	Not met	The observed population frequency is far below a stand-alone benign threshold. The highest observed gnomAD v4.1 population frequency is 1.6001e-05 (0.00160%), which is well below 1%.	gnomad_v4
BS1	Not met	The observed population frequency is too low for benign strong evidence. The highest observed gnomAD v4.1 population frequency is 1.6001e-05 (0.00160%), which is well below a 0.3% benign threshold.	gnomad_v4
BS2	Not assessed	Available population data do not establish this variant as observed in a context that would support BS2 for CHEK2-related disease.	gnomad_v4
BS3	Not assessed	No well-established functional study was identified showing that this variant has no damaging effect on CHEK2 function or splicing.	spliceai
BS4	Not assessed	No non-segregation data were identified for this variant.	clinvar
BP1	N/A	BP1 is a missense-specific criterion and does not apply to this intronic variant.
BP2	Not assessed	No phase data with another pathogenic variant were identified for this variant.
BP3	N/A	This intronic variant is not an in-frame deletion or insertion in a repetitive region.
BP4	Met	Available computational evidence supports no meaningful splice effect. SpliceAI showed a maximum delta score of 0.10, which is below commonly used thresholds for significant splice disruption and argues against an abnormal splicing effect.	spliceai
BP5	Not assessed	No alternate molecular explanation for the observed phenotype was provided, so BP5 could not be assessed.
BP6	Not assessed	This criterion was not used because assertion-based benign evidence without accessible supporting data is not considered sufficient for independent classification.	clinvar
BP7	Not met	Although SpliceAI does not predict a significant splice effect, BP7 was not applied because the reviewed evidence does not provide the additional contextual support typically used for this criterion in a noncoding intronic variant.	spliceai cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.