PPM1D c.1570del, p.(Gln524LysfsTer15)

Reasoning

The variant is extremely rare in population databases and absent from gnomAD-Canada. gnomAD v4.1 reports 2/1,614,012 alleles (AF 1.23915e-06), no homozygotes, and group maximum FAF 2.8e-07; gnomAD v2.1 reports 1/251,132 alleles (AF 3.98197e-06), no homozygotes; gnomAD-Canada v1.0 reports absence. This supports PM2 at supporting strength under the generic fallback, while the rare singleton observations and lack of disease-specific allele-frequency modeling remain threshold considerations.

Rule

Generic PM2: absent or extremely rare in population databases; for this non-VCEP fallback, allele frequency below 0.1% supports PM2 at supporting strength when population data are adequate.

Evidence considered

• gnomAD v4.1: variant present at AF 1.23915e-06 (2/1,614,012 alleles), highest observed population AF 1.69489e-06 in European non-Finnish individuals, group maximum FAF 2.8e-07, homozygotes 0.
• gnomAD v2.1: variant present at AF 3.98197e-06 (1/251,132 alleles), highest observed population AF 8.80887e-06 in European non-Finnish individuals, homozygotes 0.
• gnomAD-Canada v1.0: variant absent.
• Generic non-VCEP PM2 operating threshold: allele frequency below 0.1%; the observed frequencies are well below this threshold and there are no homozygotes.

Still missing

• No PPM1D-specific maximum credible allele frequency or penetrance model was retrieved.

Sources

Reasoning

PP5 is not met. The exact variant NM_003620.3:c.1570del is reported as absent from ClinVar, with no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification. OncoKB's variant-specific oncogenicity label is not a ClinVar expert-panel assertion and cannot trigger PP5.

Rule

Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary submissions, aggregate labels, non-expert assertions, and other databases do not qualify.

Evidence considered

• ClinVar search in the case bundle returned no exact match for NM_003620.3:c.1570del and no expert-panel classification.
• The OncoKB Likely Oncogenic label and its cited literature are not an exact-variant ClinVar expert-panel classification and were therefore excluded from PP5.

Sources

Reasoning

The variant is far below a population frequency threshold that would support BA1. gnomAD v4.1 reports an overall allele frequency of 1.23915e-06 (2/1,614,012 alleles), a maximum reported population frequency of 1.69489e-06 in the European non-Finnish population, and a group maximum FAF of 2.8e-07; gnomAD v2.1 reports 3.98197e-06 (1/251,132 alleles). These values do not approach the generic BA1 threshold of greater than 1%.

Rule

Generic BA1: allele frequency greater than 1%.

Evidence considered

• gnomAD v4.1: overall AF 1.23915e-06, 2/1,614,012 alleles; highest observed population AF 1.69489e-06 in European non-Finnish individuals; group maximum FAF 2.8e-07; homozygotes 0.
• gnomAD v2.1: overall AF 3.98197e-06, 1/251,132 alleles; highest observed population AF 8.80887e-06 in European non-Finnish individuals; homozygotes 0.
• Generic population operating threshold: BA1 requires an allele frequency greater than 1%; the observed frequencies are many orders of magnitude lower.

Sources

Reasoning

The observed population frequency does not exceed a disease-specific maximum credible frequency or the generic non-VCEP BS1 threshold of greater than 0.3%. The variant is present only at 1.23915e-06 overall AF in gnomAD v4.1, with a maximum reported population AF of 1.69489e-06, and at 3.98197e-06 overall AF in gnomAD v2.1. No frequency-based benign evidence is supported.

Rule

Generic BS1: allele frequency greater than 0.3% or above a disease-specific maximum credible frequency; no applicable disease-specific threshold was retrieved.

Evidence considered

• gnomAD v4.1: overall AF 1.23915e-06 (2/1,614,012 alleles), highest observed population AF 1.69489e-06, and group maximum FAF 2.8e-07; homozygotes 0.
• gnomAD v2.1: overall AF 3.98197e-06 (1/251,132 alleles), highest observed population AF 8.80887e-06; homozygotes 0.
• gnomAD-Canada v1.0: variant absent.
• Generic non-VCEP population operating threshold: BS1 requires an allele frequency greater than 0.3%; the observed frequencies are far below this threshold.

Sources

Reasoning

BP6 is not met. The exact variant NM_003620.3:c.1570del is absent from ClinVar, so there is no exact-variant ClinVar expert-panel Benign or Likely benign classification. Non-expert, aggregate, or other-database assertions would not qualify under the specified rule in any event.

Rule

Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary submissions, aggregate labels, non-expert assertions, and other databases do not qualify.

Evidence considered

• ClinVar search in the case bundle returned no exact match for NM_003620.3:c.1570del and no expert-panel classification.

Sources

Reasoning

No proband-level parental testing, maternity/paternity confirmation, or documented absence of the variant in both parents is provided in the case-evidence bundle. A de novo assertion therefore cannot be assessed.

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo occurrence in the affected proband with confirmed parentage; strength depends on the quality and completeness of parental testing and phenotype consistency.

Evidence considered

• The case-evidence bundle contains no documented parental testing, parentage confirmation, or de novo observation for NM_003620.3:c.1570del.

Still missing

• Documented proband status and phenotype
• Test results for both biological parents at the variant locus
• Confirmation of parentage and assessment for parental mosaicism

Reasoning

No ClinGen VCEP specification exists for PPM1D (cspec.found=false; final_classification_framework falls back to generic ACMG). Under generic ACMG/AMP, PS3 requires a well-established, variant-specific functional study showing a damaging effect. Five ONCOKB-sourced full-text papers (PMID:23907125, PMID:24880341, PMID:25742468, PMID:29954749, PMID:30304655) discuss PPM1D exon 6 truncating mutations as a class, showing that such truncations delete the C-terminal degradation domain, leading to elevated/retained phosphatase activity, gain-of-function behavior, abrogated DNA damage response, and chemoresistance in hematopoietic cells. However, a full-text search of all five papers for the exact variant identifiers (Q524, p.Gln524, c.1570del, 1570del) found zero matches in any of them -- none report this specific variant NM_003620.3:c.1570del / p.(Gln524LysfsTer15) as a tested allele. Per strict citation-grounding requirements, general gene/mutation-class-level functional discussion without the exact variant present in abstract or full text cannot be used to support PS3 for this specific variant. No variant-specific functional assay (e.g., site-directed mutagenesis of Q524Kfs*15, or an equivalent frameshift/truncation at this exact residue, in a validated phosphatase/DDR assay with appropriate wild-type and null controls) was identified in the available evidence bundle.

Evidence considered

• Full-text search of PMID:23907125, PMID:24880341, PMID:25742468, PMID:29954749, and PMID:30304655 for the strings 'Q524', 'p.Gln524', 'c.1570del', and '1570del' returned zero matches in every paper; none report the exact variant under review.
• PMID:29954749 abstract/introduction describes exon 6 PPM1D truncating mutations broadly as producing a truncated protein with elevated expression and activity due to loss of a C-terminal degradation domain, and shows these mutants confer chemoresistance in hematopoietic cells and sensitivity to a PPM1D allosteric inhibitor -- but this is class-level, not variant-specific, evidence and is not eligible to ground PS3 for this exact allele per the case's citation-grounding standard.
• PMID:25742468 abstract states PPM1D exon 6 truncating (nonsense and frameshift) mutations 'code for gain-of-function PPM1D with retained phosphatase activity,' again describing the mutation class rather than this specific variant.
• cspec.found is false in case_summary.json and vcep_materials.json confirms no PPM1D ClinGen VCEP specification/cspec URL is available, so generic ACMG/AMP PS3 rules (requiring variant-level functional evidence) apply rather than any gene-specific functional assay calibration.

Still missing

• No functional assay evidence specifically tests the p.(Gln524LysfsTer15) allele (or a molecularly equivalent PPM1D exon 6 truncation at/near codon 524) in the literature reviewed.
• Available functional papers characterize PPM1D exon 6 truncating mutations as a class (elevated phosphatase activity, GOF, chemoresistance) but do not report assay data tied to this exact variant, so they cannot be cited as PS3 grounding under strict variant-match citation rules.
• A search of ClinVar and the case's VCEP materials found no gene-specific functional assay calibration framework (no PPM1D VCEP cspec available) to define validated assay type/strength for PS3.

Sources

Reasoning

No case-control enrichment or statistically significant excess of the exact variant NM_003620.3:c.1570del was identified. The reviewed PPM1D cancer literature concerns other somatic mutations or gene-level mutation patterns and does not establish prevalence of this exact variant in affected individuals versus controls.

Rule

Generic ACMG/AMP PS4: apply only when the exact variant is observed in affected individuals at a statistically significant increased frequency compared with controls; no applicable gene-specific framework was available.

Evidence considered

• The case bundle reports no exact-variant ClinVar record and provides no case-control counts for NM_003620.3:c.1570del.
• The reviewed literature reports PPM1D mutations in cancers but does not report NM_003620.3:c.1570del as an exact germline or disease-associated case-control observation.

Still missing

• An exact-variant case series or case-control dataset with affected-individual and control counts, or a validated enrichment statistic, is unavailable.

Sources

Reasoning

No applicable PPM1D-specific VCEP framework was retrieved, so the generic ACMG/AMP framework applies. PM3 requires evidence that the tested variant is present in affected individuals with a recessive disorder and is in trans with a pathogenic or likely pathogenic variant, with phase and relevant proband observations documented. The consolidated case-evidence bundle contains no affected-proband genotype data, no candidate second pathogenic variant, no phase information, and no inheritance-mode evidence for NM_003620.3:c.1570del; therefore PM3 cannot be adjudicated.

Rule

generic_ACMG_PM3_requires_recessive_disease_and_documented_in_trans_phase

Evidence considered

• The case bundle documents NM_003620.3:c.1570del as a PPM1D frameshift, but provides no affected-proband allelic observations or segregation data.
• The case bundle provides no pathogenic/likely pathogenic second allele and no cis/trans phase determination.

Still missing

• Affected-proband observations linked to NM_003620.3:c.1570del are absent.
• No pathogenic or likely pathogenic second allele is documented.
• No parental or laboratory phase data establish the variant in trans.
• No applicable recessive inheritance model is documented for this case.

Sources

Reasoning

No case or publication evidence documents a presumed de novo occurrence without parental testing for NM_003620.3:c.1570del. PM6 cannot be assessed from the available evidence.

Rule

Generic ACMG/AMP PM6 applies only to a presumed de novo occurrence when parental testing is unavailable; the clinical and variant-level documentation must support the presumption.

Evidence considered

• The bundle provides no affected-proband case report or other documented presumed-de novo observation for this exact variant.

Still missing

• A reported affected proband with the exact variant
• Evidence supporting de novo status despite absent parental testing
• Phenotype consistency and clinical ascertainment details

Reasoning

No familial segregation data, affected relatives, unaffected relatives, informative meioses, or genotype-phenotype cosegregation observations are provided. Supporting segregation evidence cannot be assessed.

Rule

Generic ACMG/AMP PP1 requires cosegregation of the variant with disease in multiple affected family members; strength may increase with the number of informative meioses and the specificity of the phenotype.

Evidence considered

• The case-evidence bundle contains no pedigree, relative testing, meiosis count, or segregation observations for NM_003620.3:c.1570del.

Still missing

• Pedigree and number of informative meioses
• Variant testing results for affected and unaffected relatives
• Phenotype definitions and segregation concordance

Reasoning

The bundle contains no patient-level phenotype for an individual carrying the exact variant and no phenotype-specific disease presentation that can be compared with the known PPM1D disease spectrum. Gene-level cancer descriptions and functional findings are insufficient for PP4.

Rule

Generic ACMG/AMP PP4: apply only when the patient's phenotype or family history is highly specific for a disease associated with the gene; no applicable gene-specific framework was available.

Evidence considered

• The case bundle provides variant normalization and population/database findings but no clinical phenotype for an exact-variant carrier.
• The reviewed publications describe PPM1D mutation biology or tumor cohorts rather than a specific phenotype of an NM_003620.3:c.1570del carrier.

Still missing

• A documented phenotype for an exact-variant carrier and a well-established, specific phenotype association for the relevant disease are unavailable.

Sources

Reasoning

No qualifying observation of this variant in healthy adults is available. gnomAD v2.1 and v4.1 report zero homozygotes, and the two v4.1 observations are heterozygous allele counts in an unselected population rather than documented healthy-adult clinical observations. The available data therefore do not establish BS2; absence of homozygotes is not itself positive BS2 evidence.

Rule

Generic BS2: observation in healthy adults, typically multiple unaffected adults for a dominant disorder or homozygotes for a recessive disorder; unselected population allele counts alone are insufficient.

Evidence considered

• gnomAD v2.1 reports 1 total allele and 0 homozygotes; gnomAD v4.1 reports 2 total alleles and 0 homozygotes.
• The population records do not provide phenotype-confirmed healthy-adult status or the multiple unaffected-adult observations required to establish BS2.

Still missing

• No curated dataset documenting the variant in multiple healthy adults with adequate age and phenotype information was provided.
• No disease-specific penetrance, prevalence, inheritance, or healthy-control threshold for PPM1D was retrieved to determine whether heterozygous population observations could support BS2.

Sources

Reasoning

No ClinGen VCEP specification exists for PPM1D (generic ACMG fallback). BS3 requires a well-established, variant-specific functional study showing no damaging effect. None of the five functional-themed full-text papers retrieved for this case (PMID:23907125, PMID:24880341, PMID:25742468, PMID:29954749, PMID:30304655) mention this exact variant (Q524, p.Gln524KfsTer15, c.1570del), and all describe PPM1D exon 6 truncations as gain-of-function/pathogenic in mechanism, not benign. No source in the evidence bundle reports a functional assay finding this variant to be functionally neutral.

Evidence considered

• Full-text search of the five ONCOKB-linked functional papers (PMID:23907125, PMID:24880341, PMID:25742468, PMID:29954749, PMID:30304655) for this exact variant's identifiers found no matches, and no paper describes a benign/neutral functional readout for any PPM1D exon 6 truncating mutation -- the described mechanism is uniformly gain-of-function, which is inconsistent with a BS3 (benign functional evidence) determination regardless.

Still missing

• No functional assay data of any kind (benign or damaging) specific to this exact variant was identified in the reviewed literature.
• The functional literature available for PPM1D exon 6 truncations uniformly describes a gain-of-function/damaging mechanism (not neutral), so there is no basis, even at a class level, to consider a benign functional signal for this variant.

Sources

Reasoning

No tested unaffected relatives or other informative non-segregation observations are documented. Absence of segregation cannot be established, so BS4 is not assessed.

Rule

Generic ACMG/AMP BS4 requires lack of segregation in affected or informative unaffected family members, interpreted in light of age, phenotype specificity, penetrance, and ascertainment.

Evidence considered

• The case-evidence bundle contains no genotype results from unaffected relatives and no documented non-segregation observation.

Still missing

• Documented unaffected relatives who are informative for the disease
• Variant test results in those relatives
• Age, phenotype, penetrance, and relationship information sufficient to interpret non-segregation

Reasoning

No applicable PPM1D-specific VCEP framework was retrieved, so the generic ACMG/AMP framework applies. BP2 requires documented allelic configuration with another pathogenic or likely pathogenic variant: typically in trans for a fully penetrant dominant disorder, or in cis for a recessive disorder. The consolidated case-evidence bundle contains no second pathogenic/likely pathogenic variant, no cis/trans phase information, no affected-proband genotype data, and no sufficiently established inheritance model for this case; therefore BP2 cannot be adjudicated.

Rule

generic_ACMG_BP2_requires_documented_pathogenic_allelic_configuration

Evidence considered

• The case bundle contains no allelic partner, phase, or inheritance information relevant to BP2.
• The available literature packet is functional/somatic-context literature and does not provide a documented cis/trans observation for this variant.

Still missing

• A second pathogenic or likely pathogenic variant has not been documented.
• No parental or laboratory phase data establish cis or trans configuration.
• No affected-proband genotype observations are available.
• The applicable PPM1D inheritance model for this case is not documented.

Sources

Reasoning

No affected individual carrying the exact variant was documented with a clearly established alternative molecular cause of the phenotype. The available cancer literature does not provide an exact-variant BP5 observation.

Rule

Generic ACMG/AMP BP5: apply only when a variant is found in an affected individual with an alternative molecular basis for the disease; no applicable gene-specific framework was available.

Evidence considered

• The case bundle contains no exact-variant clinical case with a confirmed alternative genetic or molecular cause.

Still missing

• An exact-variant affected individual with an alternative established molecular diagnosis is unavailable.