NM_003620.3:c.1613del

PPM1D · NP_003611.1:p.(Leu538Ter) · NM_003620.3

GRCh37: chr17:58740706 AT>A · GRCh38: chr17:60663345 AT>A

Gene: PPM1D Transcript: NM_003620.3

Final call

Likely Pathogenic

PVS1_Strong PM2_Supporting

Variant details

Gene

PPM1D

Transcript

NM_003620.3

Protein

NP_003611.1:p.(Leu538Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The PPM1D NM_003620.3:c.1613del (NP_003611.1:p.(Leu538Ter), p.(L538*)) variant has been observed in somatic cancer resources as a variant-specific likely oncogenic truncating alteration and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (AF 6.19495e-07; 1/1614218 alleles), which is below the 0.1% rarity threshold and supports a rarity-based criterion.

Experimental studies of terminal truncating PPM1D variants show increased protein stability or activity and altered DNA-damage-response signaling, but the available studies do not directly test p.(Leu538Ter).

Generic PVS1 review is permitted because germline loss of function is considered an established disease mechanism for PPM1D, although distal truncating variants require manual review for appropriate strength assignment.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	This nonsense variant is predicted to truncate the PPM1D protein at p.(Leu538Ter). Generic PVS1 review is allowed because germline loss of function is considered an established disease mechanism for PPM1D, but distal truncating variants require caution under the ClinGen SVI PVS1 framework, so a downgraded PVS1 strength is more appropriate than full-strength PVS1.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing a different nucleotide change already established as pathogenic for the same protein consequence.	clinvar
PS2	Not assessed	No confirmed de novo data with parental testing were identified.
PS3	Not assessed	Available functional studies show that truncating PPM1D variants in the terminal region can increase protein stability or activity and alter DNA-damage-response signaling, but the retrieved studies do not directly test p.(Leu538Ter), so PS3 cannot be applied from the current evidence alone.	PMID:23907125 PMID:25742468 PMID:29954749 PMID:37709843
PS4	Not assessed	No case-control or statistically enriched germline case series were identified for this specific variant.	clinvar
PM1	Not met	Available hotspot review did not identify this variant in a statistically significant hotspot, so current evidence does not support PM1.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 at AF 6.19495e-07 (0.00006%, 1/1614218 alleles), which is below the 0.1% rarity threshold and supports PM2.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with another pathogenic variant in a recessive disease context.
PM4	N/A	PM4 is not applicable because this is a nonsense variant already evaluated under the loss-of-function framework rather than an in-frame length-changing variant.	pvs1_variant_assessment
PM5	N/A	PM5 is not applicable because this criterion is for novel missense changes at a residue with a different pathogenic missense change, and this variant is a nonsense change.	pvs1_variant_assessment
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified.
PP1	Not assessed	No segregation data were identified.
PP2	N/A	PP2 is not applicable because this variant is not a missense change.	pvs1_variant_assessment
PP3	N/A	PP3 is not applicable because this variant is a nonsense deletion with a direct predicted truncating effect, so missense or splice prediction algorithms are not the primary evidence source for interpretation.	pvs1_variant_assessment
PP4	Not assessed	No phenotype information was provided that would allow assessment of a highly specific PPM1D-related clinical presentation.
PP5	Not assessed	No reputable pathogenic classification from an external clinical database was identified because this variant is absent from ClinVar.	clinvar
BA1	Not met	The observed population frequency is far below the benign stand-alone threshold: gnomAD v4.1 AF is 6.19495e-07 (0.00006%), which is below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	The observed population frequency does not exceed the strong benign threshold: gnomAD v4.1 AF is 6.19495e-07 (0.00006%), which is below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals at a frequency expected to argue against pathogenicity.	gnomad_v4
BS3	Not met	Available functional studies do not show normal PPM1D function for this class of truncating variants; instead they report abnormal increased activity or altered stress-response signaling, so BS3 is not supported.	PMID:23907125 PMID:25742468 PMID:29954749 PMID:37709843
BS4	Not assessed	No data were identified showing lack of segregation with disease in a family.
BP1	N/A	BP1 is not applicable because this variant is not a missense change.	pvs1_variant_assessment
BP2	Not assessed	No phase data were identified to show this variant in cis with a pathogenic variant or in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	Not assessed	No evidence was identified showing that this variant lies in a repetitive region without known function.
BP4	N/A	BP4 is not applicable because this variant is a nonsense deletion and not a missense or synonymous change suited to benign computational prediction frameworks.	pvs1_variant_assessment
BP5	Not assessed	No alternate molecular explanation was provided that would account for the phenotype independently of this variant.
BP6	Not assessed	No reputable benign classification from an external clinical database was identified because this variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 is not applicable because this variant is neither synonymous nor an intronic change outside the canonical splice region.	pvs1_variant_assessment

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