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]
  • See Evidence submitted by expert panel for details.

Variant: NM_000314.6(PTEN):c.284C>T (p.Pro95Leu)

CA000383

189403 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 43eee6bc-e0e1-4ce0-8d9a-b838428c1884
Approved on: 2019-06-25
Published on: 2019-07-23

HGVS expressions

NM_000314.6:c.284C>T
NM_000314.6(PTEN):c.284C>T (p.Pro95Leu)
NC_000010.11:g.87933043C>T
CM000672.2:g.87933043C>T
NC_000010.10:g.89692800C>T
CM000672.1:g.89692800C>T
NC_000010.9:g.89682780C>T
NG_007466.2:g.74605C>T
NM_000314.5:c.284C>T
NM_001304717.2:c.803C>T
NM_001304718.1:c.-467C>T
NM_000314.7:c.284C>T
NM_001304717.5:c.803C>T
NM_001304718.2:c.-467C>T
ENST00000371953.7:c.284C>T
ENST00000498703.1:n.110C>T
ENST00000610634.1:c.182C>T
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Pathogenic

Met criteria codes 5
PP2 PM2 PM6 PS4_Supporting PS3
Not Met criteria codes 17
PP3 PP1 PM4 PM5 PM1 BS2 BS1 BS3 BS4 BP4 BP2 BP7 BP5 BA1 PVS1 PS2 PS1

Evidence Links 7

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
PTEN VCEP
PTEN c.284C>T (p.Pro95Leu) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3: Phosphatase activity <50% of wild type (PMID 21828076, PMID 29706350) PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID 26957) 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor ClinVar Organization ID 26957)
Met criteria codes
PP2
KS agrees.
PM2
Variant is not present in gnomAD. KS agrees.
PM6
Internal case from GeneDx: male child with macrocephaly, developmental delay and penile freckling (pediatric proband specificity score = 7).
PS4_Supporting
Heald B et al. in a prospective series of PTEN mutation carriers reported subject 1515 has having > 50 hamartomas. The Herman Laboratory Nationwide Children's Hospital reported clinical data into Clinvar. The patient had macrocephaly (+6.4 SD) and > 40 colon polyps and 15 were > 1cm and all were juvenile polyps. It is unclear whether this patient is the same as the patient reported in Heald B et al. Tan et. al reported individual 20 as meeting relaxed International Consortium operational criteria for PTHS. Could meet PS4_S but need more phenotype information. Entry by MPerpich. KS: GeneDx internal data: male child with macrocephaly, penile freckling, developmental delay and pediatric proband score = 7. This case is also de novo, and reaches 1 phenotype specificity point. A second case of a female in her 40's with breast cancer and 3 colon polyps (adenomatous and hyperplastic). PTEN study data: Very likely this is the same patient as Heald et al., OFC = 60 cm, GI hamartomas (6), and GI poylps NOS (44), and CC score = 22.
Variant identified in 2 individuals in study. PubMed:21659347
Likely is the same patient as Heald et al. and Tan et al. PubMed:25669429
PubMed:20600018
PubMed:21194675
Macrocephaly (+6.4 SD); Colonoscopy with >40 polyps throughout the colon, 15 were >1cm, all were jevenile type. PubMed:28526761
PS3
Escudero et al. (2011) demonstrated a high percentage of PIP3+ cells (similar to vector), no growth rescue and reduced PTEN activity in figure 4. Miguel et al. (2018) classified variant as truncation-like with a G score of -3.414242736. MPerpich entry. KS agrees. Matreyek results not available.
PubMed:29706350
PubMed:21828076
Not Met criteria codes
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
ClinVar entry for Pro95Thr, however that variant not is reported in the literature. Likely will not meet likely pathogenic/pathogenic at this time. May be reasonable to re-evaluate in future.
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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