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.392C>T (p.Thr131Ile)

CA000442

39669 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 78613fd1-ded6-4249-b54d-0894617cf17d
Approved on: 2018-11-28
Published on: 2018-12-10

HGVS expressions

NM_000314.6:c.392C>T
NM_000314.6(PTEN):c.392C>T (p.Thr131Ile)
NM_000314.5:c.392C>T
NM_001304717.2:c.911C>T
NM_001304718.1:c.-359C>T
NM_000314.7:c.392C>T
NM_001304717.5:c.911C>T
NM_001304718.2:c.-359C>T
ENST00000371953.7:c.392C>T
ENST00000498703.1:n.218C>T
ENST00000610634.1:c.290C>T
NC_000010.11:g.87933151C>T
CM000672.2:g.87933151C>T
NC_000010.10:g.89692908C>T
CM000672.1:g.89692908C>T
NC_000010.9:g.89682888C>T
NG_007466.2:g.74713C>T
More

Pathogenic

Met criteria codes 5
PM6_Strong PS4_Moderate PM2 PS3 PP2
Not Met criteria codes 18
BS1 BS3 BS4 BS2 BP7 BP5 BP4 BP2 PM5 PM4 PM1 PS1 PS2 BA1 PP3 PP4 PP1 PVS1

Evidence Links 6

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
PTEN VCEP
PTEN c.392C>T (p.Thr131Ile) 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) PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (PMID 23160955, 23335809 author communication) PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 23160955, 23335809) 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.
Met criteria codes
PM6_Strong
De novo variant identified in Cauc male with autism, non-verbal IQ=50. OFC 57.8 cm at or under 4 yrs old. At least +5SD, z-score +4.7 per article. Pt in study via Simons Simplex Collection. Pt ID 14433.p1. Pt tested via exome but parents tested targeted only. PubMed:23160955
Info unpublished, but per Dr. Longy, parents of pt 74 are unaffected and both negative for variant. PubMed:23335809
Reported de novo variant in child with macrocephaly and autism; variant absent in a sibling, affected status unknown. Pts recruited from National Database for Autism research BUT study ID (14 433) way too similar to O'Roak, appears to be same individual. PubMed:28250423
PS4_Moderate
JM: bumped up to PS4_moderate with 2 total phenotype points (1 for Bubien, 1 for O'Roak)
Identified in child with extreme macrocephaly and autism. See de novo section. 1 point. Patient was reported as male with speech delay, low verbal and non-verbal IQ PubMed:23160955
Identified in pts 73/74 (child and parent). Child is proband pt 73, had macrocephaly (55.5cm) and MR/autism/ADD. Parent had targeted testing, history of macrocephaly (62cm) , polyps (pseudo polyps and lymphoid hyperplasia), benign thyroid (MNG) and breast disease (mild fibrocystic mastopathy). Reached out to Dr. Longy for details: Dear Jessica, Thank for your note. I confirm that patient 73 is the son of patient 74. Patient 73: born in 2002, observed in 2005 (3 years old). Macrocephaly: 55.5 cm (+4DS); delay in acquisitions and attention deficit. Patient 74: born In 1974, observed in 2005 (31 years old). Macrocephaly: 62 cm; colonoscopy in 2007 showing pseudo polyps with lymphoid hyperplasia, unoperated thyroid goiter and mild fibrocystic mastopathy. To note that the father and the mother of patient 74 , phenotypically normal, are non-carrier of the PTEN T131I. To note also that I was contacted by William Foulkes in 2015 because he had to follow a boy with the same mutation and autism disorder. PubMed:23335809
PM2
Absent in gnomAD
PS3
Variant categorized as "WT-like" on VAMPseq high throughput assay assessing protein abundance as a measure of stability. PubMed:29785012
Variant demonstrated loss of phosphatase activity on in vitro assay, also showed lack of growth rescue capability. PubMed:21828076
Variant in hypomorphic range (score -1.91) on high-throughput phosphatase assay PubMed:29706350
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Not Met criteria codes
BS1
Absent in gnomAD
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
BS2
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
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
PM5
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
PM1
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
PS2
De novo variant identified in Cauc male with autism, non-verbal IQ=50. OFC 57.8 cm at or under 4 yrs old. At least +5SD, z-score +4.7 per article. Pt in study via Simons Simplex Collection. Pt ID 14433.p1. Pt tested via exome but parents tested targeted only. PubMed:23160955
Info unpublished, but per Dr. Longy, parents of pt 74 are unaffected and both negative for variant. PubMed:23335809
Reported de novo variant in child with macrocephaly and autism; variant absent in a sibling, affected status unknown. Pts recruited from National Database for Autism research BUT study ID (14 433) way too similar to O'Roak, appears to be same individual. PubMed:28250423
BA1
Absent in gnomAD
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
Individual 73 has macrocephaly (55.5cm) and ADD/autism which provides a CC score of 5 or 1 point or PP4. Moved to PS4.
See explanation PubMed:23335809
PP1
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
Curation History
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