NM_014225.5:c.536C>G

PPP2R1A · NP_055040.2:p.(Pro179Arg) · NM_014225.5

GRCh37: chr19:52715971 C>G · GRCh38: chr19:52212718 C>G

Gene: PPP2R1A Transcript: NM_014225.5

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM2 moderate

Variant details

Gene

PPP2R1A

Transcript

NM_014225.5

Protein

NP_055040.2:p.(Pro179Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_014225.5:c.536C>G (p.Pro179Arg) in PPP2R1A is classified as Likely Pathogenic per ACMG/AMP 2015 generic framework.

PS3 (Strong): Direct functional characterization of P179R via X-ray crystallography, co-immunoprecipitation, phosphatase assays, and patient-derived tumor models demonstrates unequivocal disruption of PP2A holoenzyme assembly, loss of catalytic subunit binding, and tumorigenic potential.

PM1 (Moderate): Residue P179 is a statistically significant mutational hotspot (cancerhotspots.org) within HEAT domain 5, a critical functional domain of the PP2A Aα scaffolding subunit.

PM2 (Moderate): Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency <0.1%).

Combined evidence (1 Strong + 2 Moderate) meets the ACMG/AMP 2015 threshold for Likely Pathogenic classification.

This variant has been observed somatically in 92 cancer specimens (COSMIC COSV59042232) and is the most recurrent PPP2R1A mutation in high-grade endometrial carcinoma, though germline clinical classification is based on the functional and population evidence cited above.

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	Not met	NM_014225.5:c.536C>G is a missense variant (p.Pro179Arg) and does not fall into null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus) required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	No evidence of an alternate nucleotide change at codon 179 producing the same p.Pro179Arg substitution that has been classified as pathogenic.
PS2	Not met	No de novo observation with confirmed maternity and paternity has been reported for NM_014225.5:c.536C>G (p.Pro179Arg).
PS3	Met	P179R was directly tested in PMID:31142515 via X-ray crystallography (PDB 6EF4, 3.4Å resolution), co-immunoprecipitation, phosphatase activity assays, molecular dynamics simulations, and patient-derived endometrial carcinoma models (UT89, UT42). P179R disrupts PP2A holoenzyme assembly by altering Aα-subunit conformation, near-completely abolishes catalytic C-subunit binding, promotes proteasome-mediated C-subunit degradation, and reduces PP2A phosphatase activity. Restoration of wild-type Aα in P179R-mutant patient-derived cells suppresses tumorigenic features in xenograft assays. The functional effect is unequivocal and directly demonstrated for the exact variant.	PMID:31142515 PMID:40604275
PS4	Not met	No case-control prevalence data comparing affected individuals to controls is available for this variant.
PS5	N/A	PS5 is not a standard criterion in the ACMG/AMP 2015 generic framework (Richards et al. 2015, PMID:25741868); no VCEP-specific PS5 definition exists for PPP2R1A.	generic_acmg_combination_rules
PM1	Met	Residue P179 is a statistically significant mutational hotspot (cancerhotspots.org) and lies within HEAT domain 5 of the PP2A Aα scaffolding subunit, a critical functional domain for PP2A holoenzyme assembly. PMID:31142515 identifies P179 as the most recurrent PPP2R1A mutation site in high-grade endometrial carcinoma (48 of 51 reported P179 mutations are P179R). No benign variation has been reported at this residue in population databases.	PMID:31142515
PM2	Met	NM_014225.5:c.536C>G is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold of <0.1% allele frequency in large population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue (P179) comparator variant with a pathogenic classification in ClinVar was identified; automated PM5 candidate harvesting yielded no candidates. Other P179 variants (P179L, P179T, P179H) have been reported in the literature as somatic mutations but lack germline pathogenic classification in ClinVar.	pm5_candidates
PM6	Not met	No de novo observation (without confirmed maternity/paternity) has been reported for NM_014225.5:c.536C>G.
PP1	Not met	No co-segregation data with disease in multiple affected family members is available for this variant.
PP2	Not met	No gene-level missense constraint metric (e.g., gnomAD missense Z-score or HCI prior probability) is available to establish that PPP2R1A has a low rate of benign missense variation. HCI prior lookup returned 'gene_not_supported'.
PP3	Not met	Computational predictors do not support a deleterious effect. REVEL score is 0.386 (below 0.5 threshold), BayesDel score is 0.123, and SpliceAI max delta is 0.01 (no splicing impact). Multiple lines of computational evidence do not support PP3.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data or family history specific to a disease with single genetic etiology is available for this variant.
PP5	Not met	NM_014225.5:c.536C>G is absent from ClinVar with no classification from any submitter. PP5 requires a reputable source (≥3-star ClinVar expert panel) to have reported the variant as pathogenic. OncoKB classification ('Likely Oncogenic') is a somatic cancer database and does not qualify as a germline ClinVar expert panel classification.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the BA1 threshold of 1% in any population database.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the BS1 threshold of 0.3% in any population database.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of this variant in a homozygous or hemizygous state in healthy adults has been reported.
BS3	Not met	Functional evidence from PMID:31142515 demonstrates a clear damaging loss-of-function effect: P179R disrupts PP2A holoenzyme assembly, reduces phosphatase activity, and promotes tumorigenesis. This directly contradicts a benign functional interpretation.	PMID:31142515
BS4	Not met	No segregation data in affected families is available to assess lack of segregation with disease.
BP1	Not met	PPP2R1A-related neurodevelopmental disorder (Houge-Janssens syndrome type 2, HJS2) is primarily caused by missense variants (PMID:37945024, PMID:40781915). Missense variants are a well-established disease mechanism for this gene; BP1, which applies when primarily truncating variants cause disease, does not apply.
BP2	Not met	No phase data (in trans or in cis with a pathogenic variant) is available for this variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this variant is a missense substitution.
BP4	Not met	Computational evidence is not consistently benign across tools. REVEL score of 0.386 is in a gray zone (below 0.5 but not definitively benign), BayesDel score of 0.123 is low, and SpliceAI max delta is 0.01. The mixed signal precludes a confident BP4 assignment.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6	Not met	NM_014225.5:c.536C>G is absent from ClinVar with no classification from any submitter. BP6 requires a reputable source (≥3-star ClinVar expert panel) to have reported the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact; NM_014225.5:c.536C>G is a missense variant (p.Pro179Arg).

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