Variant classification summary

NM_001274.5:c.484C>T

CHEK1 · NP_001265.2:p.(Arg162Cys) · NM_001274.5

GRCh37: chr11:125503117 C>T · GRCh38: chr11:125633222 C>T

Gene: CHEK1 Transcript: NM_001274.5

Final call

VUS

PM2 supporting

Variant details

Gene

CHEK1

Transcript

NM_001274.5

Protein

NP_001265.2:p.(Arg162Cys)

gnomAD AF

1.2466107769501667e-05 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 overall allele frequency is 0.00125%, below the 0.1% rarity threshold, with no homozygotes.

2

Final: only PM2 is met at supporting strength, no ACMG/AMP 2015 combination rule is satisfied, and the variant is classified as Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback: with only PM2 (supporting) met and no other criteria met, none of the Pathogenic/Likely Pathogenic/Benign/Likely Benign combination thresholds are reached, so the variant is classified as 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	Not applicable: as a missense substitution, it does not trigger a null-variant mechanism such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no ClinVar record exists for this position, and no established pathogenic variant producing p.(Arg162Cys) from a different nucleotide change was found.	clinvar
PS2	Not assessed	Not assessed: no parental testing or parentage-confirming evidence was available, so a de novo origin cannot be established.
PS3	Not assessed	Not assessed: no functional or biochemical assay data specific to p.(Arg162Cys) was available.
PS4	Not assessed	Not assessed: no case-control data or variant-specific enrichment analysis for c.484C>T was provided.
PM1	Not assessed	Not assessed: no curated hotspot/domain definition is available, and cancerhotspots.org does not list this position as a statistically significant hotspot.	oncokb
PM2	Met	Met (supporting): gnomAD v4.1 overall allele frequency is 0.00125%, far below the 0.1% PM2 rarity threshold, with no homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband data places this variant in trans with a pathogenic CHEK1 variant.	clinvar generic_acmg_combination_rules
PM4	N/A	Not applicable: this missense substitution does not change protein length, leaving nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no established pathogenic missense variant at codon 162 was identified.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no parental testing result is present, so a presumed de novo occurrence cannot be determined.
PP1	Not assessed	Not assessed: no family segregation data or informative meioses were available.
PP2	Not assessed	Not assessed: no CHEK1-specific guidance or missense-constraint data establishes missense as a common disease mechanism.	oncokb
PP3	Not met	Not met: REVEL score 0.437 falls within the gray zone (0.250-0.750), providing no in-silico support for pathogenicity.	revel
PP4	Not assessed	Not assessed: no proband phenotype indicating a CHEK1-specific presentation was provided.
PP5	Not met	Not met: the exact variant has no ClinVar record, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: highest population frequency is 0.00450% (East Asian), far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest ancestry-specific frequency is 0.00450%, below the 0.3% BS1 benign threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no phenotype-confirmed healthy adult carriers were documented; sparse heterozygous observations alone are insufficient.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific functional assay data for p.(Arg162Cys) was available to demonstrate normal function.
BS4	Not assessed	Not assessed: no genotype-positive unaffected or genotype-negative affected relatives were documented.
BP1	Not assessed	Not assessed: no quantitative data confirms that missense variants are not a common cause of CHEK1 disease.
BP2	Not assessed	Not assessed: no phase or pedigree data places this variant in cis or trans with a pathogenic CHEK1 variant.	clinvar generic_acmg_combination_rules
BP3	N/A	Not applicable: this missense substitution is not an in-frame insertion/deletion in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL score 0.437 is above the <0.250 BP4 threshold required for benign in-silico support.	revel
BP5	Not assessed	Not assessed: no alternate molecular diagnosis providing another basis for disease was documented.
BP6	Not met	Not met: the exact variant has no ClinVar record, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: this criterion applies to synonymous variants, and this missense substitution alters the protein sequence.	generic_acmg_combination_rules

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