Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • Despite there being a valid 'cspec' property in the messages there's a discrepancy in message contents and CSPEC data: * Message Gene: PTEN CSPEC Genes: [ 'PTEN' ] * Message MONDOs: MONDO:0017623 CSPEC MONDO: []
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000314.8(PTEN):c.476G>A (p.Arg159Lys)

CA377482801

646006 (ClinVar)

Gene: PTEN (HGNC:5728)
Condition: PTEN hamartoma tumor syndrome (MONDO:0017623)
Inheritance Mode: Autosomal dominant inheritance
UUID: 4cd22c47-1e9d-469a-8faf-fd5b3fcf863e
Approved on: 2025-10-03
Published on: 2025-10-27

HGVS expressions

NM_000314.8(PTEN):c.476G>A (p.Arg159Lys)
NM_000314.8:c.476G>A
NC_000010.11:g.87933235G>A
CM000672.2:g.87933235G>A
NC_000010.10:g.89692992G>A
CM000672.1:g.89692992G>A
NC_000010.9:g.89682972G>A
NG_007466.2:g.74797G>A
ENST00000700029.2:c.476G>A
ENST00000710265.1:c.476G>A
ENST00000472832.3:c.476G>A
ENST00000688158.2:n.1211G>A
ENST00000688922.2:c.*306G>A
ENST00000700021.1:c.431G>A
ENST00000700022.1:c.476G>A
ENST00000700029.1:c.310G>A
ENST00000706954.1:c.476G>A
ENST00000706955.1:c.*511G>A
ENST00000686459.1:c.476G>A
ENST00000688158.1:c.*587G>A
ENST00000688308.1:c.476G>A
ENST00000688922.1:c.397G>A
ENST00000693560.1:c.995G>A
ENST00000371953.8:c.476G>A
ENST00000371953.7:c.476G>A
ENST00000498703.1:n.302G>A
ENST00000610634.1:c.374G>A
NM_000314.5:c.476G>A
NM_000314.6:c.476G>A
NM_001304717.2:c.995G>A
NM_001304718.1:c.-275G>A
NM_000314.7:c.476G>A
NM_001304717.5:c.995G>A
NM_001304718.2:c.-275G>A
More

Pathogenic

Met criteria codes 6
PM6_Strong PS4_Moderate PP3 PP2 PS3_Moderate PM2_Supporting
Not Met criteria codes 2
BS2 PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
PTEN VCEP
PTEN c.476G>A (p.Arg159Lys) meets criteria to be classified as Pathogenic for PTEN hamartoma tumor syndrome in a autossomal dominant manner under ACMG criteria for PTEN gene v3 (PMID:30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_M: Phosphatase activity <-1.11 per Mighell et al. 2018 (PMID: 29706350). PP2: PTEN classified as a gene with missense variants that have low rate of benign missense variation and where missense variants are common mechanisms of disease. PP3: REVEL score (0.961) greater than 0.7. PM2_P: Variant absent on gnomad (v4). PM6_S: Assumed de novo case with strong PTEN-specific phenotype in patient (reported with extreme macrocephaly, autism and developmental delay, and seizures (Pediatric score +5) (internal laboratory contributor). PS4_M: Pediatric patient reported in Tuli et al. (PMID: 34184188) to have neonatal overgrowth, macrocephaly (+5.6 SD), developmental delay and periventricular leukomalacia.(Pediatric score +5. +1 proband point). Pediatric patient reported with developmental delay, macrocephaly and polymicrogyria. (Pediatric score +6, +1 proband point) (Internal laboratory contributor).
Met criteria codes
PM6_Strong
Assumed de novo pediatric patient with highly specific phenotype: macrocephaly, autism and developmental delay, and seizures (Pediatric score +5, meets PS4 criteria). (internal laboratory contributor).
PS4_Moderate
Pediatric patient reported in Tuli et al. (PMID: 34184188) to have neonatal overgrowth, macrocephaly (+5.6 SD), developmental delay and periventricular leukomalacia. (Pediatric score +5. +1 proband point). Pediatric patient reported with developmental delay, macrocephaly and polymicrogyria. (Pediatric score +6, +1 proband point) (Internal laboratory contributor).
PP3
REVEL score (0.961) greater than 0.7.
PP2
PTEN classified as a gene with missense variants that have low rate of benign missense variation and where missense variants are common mechanisms of disease.
PS3_Moderate
Phosphatase activity <-1.11 per Mighell et al. 2018 (PMID: 29706350).
PM2_Supporting
Variant absent on gnomad (v4).
Not Met criteria codes
BS2
Observed in one unaffected individual without homozygous status confirmed. (internal communication)
PM5
Novel missense change at amino acid position where different missense change has been deemed likely pathogenic. PTEN c.477G>T (p.Arg159Ser) classified as likely pathogenic by Clingen PTEN Variant Curation Panel. BLOSUM 62 score for Arg/Lys change greater than Arg/Ser change, due to this weight for PM5_M is not applied.
Curation History
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