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.355G>T (p.Val119Phe)

CA377482258

428193 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d34e6361-5beb-4bbe-8bea-c9891ddec52e
Approved on: 2025-12-05
Published on: 2025-12-17

HGVS expressions

NM_000314.8:c.355G>T
NM_000314.8(PTEN):c.355G>T (p.Val119Phe)
NC_000010.11:g.87933114G>T
CM000672.2:g.87933114G>T
NC_000010.10:g.89692871G>T
CM000672.1:g.89692871G>T
NC_000010.9:g.89682851G>T
NG_007466.2:g.74676G>T
ENST00000700029.2:c.355G>T
ENST00000710265.1:c.355G>T
ENST00000472832.3:c.355G>T
ENST00000688158.2:n.1090G>T
ENST00000688922.2:c.*185G>T
ENST00000700021.1:c.310G>T
ENST00000700022.1:c.355G>T
ENST00000700029.1:c.189G>T
ENST00000706954.1:c.355G>T
ENST00000706955.1:c.*390G>T
ENST00000686459.1:c.355G>T
ENST00000688158.1:c.*466G>T
ENST00000688308.1:c.355G>T
ENST00000688922.1:c.276G>T
ENST00000693560.1:c.874G>T
ENST00000371953.8:c.355G>T
ENST00000371953.7:c.355G>T
ENST00000498703.1:n.181G>T
ENST00000610634.1:c.253G>T
NM_000314.5:c.355G>T
NM_000314.6:c.355G>T
NM_001304717.2:c.874G>T
NM_001304718.1:c.-396G>T
NM_000314.7:c.355G>T
NM_001304717.5:c.874G>T
NM_001304718.2:c.-396G>T
More

Likely Pathogenic

Met criteria codes 5
PP3 PP2 PM2 PM5 PS3_Moderate
Not Met criteria codes 3
PS4 PP1 PP4

Evidence Links 1

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.355G>T (p.Val119Phe) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -2.07 (≤ -1.11) on a high throughput phosphatase assay (PMID 29706350). PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 3256748). PP3: REVEL score > 0.7 (score of this variant = 0.966). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PM2_P: Absent in large sequenced populations (PMID 27535533).
Met criteria codes
PP3
REVEL score (0.966) > 0.7
PP2
Missense
PM2
Absent in gnomAD v2 and v4
PM5
BLOSUM score for focal variant (V>F: -1) ≤ BLOSUM score for 1 close match (V>A: 1) recently classified as LP (discussed at 4/4/25 VCEP meeting, pending approval in VCI).
PS3_Moderate
Data from Mighell et al. is now eligible for PS3_Moderate (see update below).
High throughput functional study to test lipid phosphatase activity using artificial humanized yeast model. The fitness score was -2.067 (true) for this variant which is in hypomorphic/inconclusive range (less than -2.13 would be truncation-like). Update: Based on PTEN VCEP criteria v3.1.0, the Mighell data is now eligible for PS3_M (Phosphatase activity ≤ -1.11) PubMed:29706350
Not Met criteria codes
PS4
Several probands with clinical evidence but not enough to contribute towards classification: Cleveland Clinic (Dr. Lamis Yehia pers comm): F in 40s w/ Macrocephaly (OFC 59 cm), Thyroid nodule, Hashimoto disease, breast fibrocystic disease, Lipoma, Hyperplastic benign polyp, Ovarian cysts, Pulmonary nodule, Oral mucosa papilloma, Uterine fibroids CC score = 19 Ambry (internal): F w/ renal ca @ 30s, bilateral breast ca @50s, endo ca @ 50s, HC = 60.96 cm (>95%), skin tags, one lipoma, thyroid nodules, oral lesions, colon polyps (“HP”, path data not available) CC score = 18. Proband’s sister (pos for variant): breast ca @ 50s, endo & ovarian ca @ 50s, 1 lipoma, HC = 58.42 cm, 6 colon polyps (“HP”) CC score = 15 Ambry (external data share): Proband (< 10 yo) w/ HC +3.3 SD. Family Hx: Mother (30s) w/ HC +2.2 SD, thyroid goiter; Grandmother ‘typical PHTS’ according to PTEN specialist - macrocephaly, obese, trichillemmomas in face, high philtrum, gum hypertrophy, tongue papillomas, papillomas in mucosa CC score = 22;
PP1
Ambry (1 meiosis): Proband (F) w/ renal ca @ 30s, bilateral breast ca @50s, endo ca @ 50s, HC = 60.96 cm (>95%), skin tags, one lipoma, thyroid nodules, oral lesions, colon polyps (“HP”, path data not available). Family Hx: Sister (pos for variant) w/ breast ca @ 50s, endo & ovarian ca @ 50s, 1 lipoma, HC = 58.42 cm, 6 colon polyps (“HP”); Brother (neg for variant) w/ colon polyps (3 villous adenoma @40s, 2 pre-cancerous @50s), skin lesions (unknown type); Mother (not tested-deceased) w/ breast ca @30s, endo @ 40s, CRC @ 60s. Ambry (external data share): Variant reported to segregate in one family, but variant carrier status not confirmed. Proband (< 10 yo) w/ HC +3.3 SD. Family Hx: Mother (30s) w/ HC +2.2 SD, thyroid goiter; Grandmother (GM) w/ ‘typical PHTS’ according to PTEN specialist (macrocephaly, obese, trichillemmomas in face, high philtrum, gum hypertrophy, tongue papillomas, papillomas in mucosa); GM’s sister w/ multinodular struma, bilateral breast ca @ 40s (BRCA1/2 neg), obese, dysmorphic features; GM’s sister’s daughter w/ obese, thyroid problems (removed partially), hyperthyroidemia.
PP4
Ambry #1 Female dx with renal ca in 30s, bilateral breast ca in 50s, endometrial ca in 50s, head circumference 60.96 cm (>95%), skin tags, one lipoma, thyroid nodules, oral lesions, colon polyps (per clinical notes they needed to check path). CC score is too low at 18-24 depending on polyp number. Sister (POSITIVE): breast ca in 50s, endometrial ca in 50s, and ovarian ca in 50s, one lipoma, head circumference 58.42 cm, 6 colon polyps; Brother (NEGATIVE): colon polyps (3 villous adenomas in 40s, 2 pre-cancerous polyps in 50s), skin lesions (unknown type); Mother (not tested--deceased): breast ca in 30s, endometrial ca in 40s, and CRC in 60s.
Curation History
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