Variant classification summary

NM_003620.3:c.1570del

PPM1D · NP_003611.1:p.(Gln524LysfsTer15) · NM_003620.3

GRCh37: chr17:58740662 GC>G · GRCh38: chr17:60663301 GC>G

Gene: PPM1D Transcript: NM_003620.3

Final call

VUS

PM2 supporting

Variant details

Gene

PPM1D

Transcript

NM_003620.3

Protein

NP_003611.1:p.(Gln524LysfsTer15)

gnomAD AF

1.2391481599888972e-06 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely rare in population databases - 2/1,614,012 gnomAD v4.1 alleles (AF 1.24e-06) and absent from gnomAD-Canada.

2

Overall: VUS - a single supporting pathogenic criterion (PM2) is insufficient to reach likely pathogenic under the generic ACMG/AMP 2015 combination rules.

Final determination: A single PM2 supporting criterion meets none of the generic ACMG/AMP combination thresholds for LP/P or LB/B, so the variant is VUS.

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: this terminal-exon frameshift is predicted to escape nonsense-mediated decay, and the established PPM1D mechanism for this class is gain-of-function rather than loss-of-function.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework PMID:23907125 PMID:24880341 PMID:25742468 PMID:29954749 PMID:30304655
PS1	N/A	Not applicable: as a frameshift, no altered amino acid exists at this position to compare against a previously established pathogenic missense change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing or documented absence of the variant in both parents was available to support a de novo assertion.
PS3	Not assessed	Not assessed: no functional study of this exact variant exists; five PPM1D papers cover the truncation class but never test c.1570del.
PS4	Not assessed	Not assessed: no case-control data or statistically significant enrichment of this exact variant in affected individuals was identified.
PM1	N/A	Not applicable: as a frameshift, no altered residue exists to evaluate for mutational-hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (supporting): present in only 2/1,614,012 gnomAD v4.1 alleles (AF 1.24e-06) and absent from gnomAD-Canada.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no proband genotype data, no second pathogenic variant, and no phase information were available for trans testing.	generic_acmg_combination_rules
PM4	N/A	Not applicable: as a frameshift, no in-frame protein length change occurs for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: as a frameshift, no missense change exists at this residue to compare against a known pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no case or publication documents a presumed de novo occurrence of this variant without parental testing.
PP1	Not assessed	Not assessed: no familial segregation data or informative meioses were available to support cosegregation.
PP2	N/A	Not applicable: as a frameshift, the gene's missense-constraint properties are irrelevant since no missense change exists to evaluate.	generic_acmg_combination_rules
PP3	N/A	Not applicable: frameshift falls outside the calibrated missense/splice scope, and SpliceAI predicts no splice impact (max delta 0.001).	spliceai
PP4	Not assessed	Not assessed: no patient-level phenotype for a carrier of this exact variant was available to compare with the PPM1D disease spectrum.
PP5	Not met	Not met: the exact variant is absent from ClinVar, and OncoKB's oncogenicity label is not an expert-panel assertion.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 1.24e-06 is far below the >1% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD allele frequency 1.24e-06 is far below the >0.3% BS1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no documented observations of this variant in healthy adults; absence of homozygotes is not positive evidence.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional study shows this exact variant is functionally neutral; available literature describes this truncation class as gain-of-function.
BS4	Not assessed	Not assessed: no tested unaffected relatives or non-segregation observations were documented.
BP1	N/A	Not applicable: as a frameshift, there is no missense change for this truncating-mechanism criterion to evaluate.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second pathogenic variant, phase information, or inheritance model was available to evaluate allelic configuration.	generic_acmg_combination_rules
BP3	N/A	Not applicable: as a frameshift, there is no in-frame repeat-region length change for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: frameshift falls outside the calibrated in-silico scope, and the null SpliceAI result (max delta 0.001) adds no independent benign evidence.	spliceai
BP5	Not assessed	Not assessed: no carrier with a clearly established alternative molecular cause of their phenotype was documented.
BP6	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel benign classification exists.	clinvar
BP7	N/A	Not applicable: as a frameshift, the encoded protein is altered, so the silent-variant premise does not hold.	generic_acmg_combination_rules

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.