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_000314.7(PTEN):c.493G>A (p.Gly165Arg)

CA377484223

428256 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 7dfd587f-6e05-448b-b023-de30c0bfd916
Approved on: 2019-11-22
Published on: 2020-01-02

HGVS expressions

NM_000314.7:c.493G>A
NM_000314.7(PTEN):c.493G>A (p.Gly165Arg)
NC_000010.11:g.87952118G>A
CM000672.2:g.87952118G>A
NC_000010.10:g.89711875G>A
CM000672.1:g.89711875G>A
NC_000010.9:g.89701855G>A
NG_007466.2:g.93680G>A
NM_000314.5:c.493G>A
NM_000314.6:c.493G>A
NM_001304717.2:c.1012G>A
NM_001304718.1:c.-99G>A
NM_001304717.5:c.1012G>A
NM_001304718.2:c.-99G>A
ENST00000371953.7:c.493G>A
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Pathogenic

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

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
PTEN VCEP
PTEN c.493G>A (p.Gly165Arg) 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor SCV000617324.2) PS3: Phosphatase activity <50% of wild type (PMID 29706350, 9256433, 10866302) PM2: Absent in large sequenced populations (PMID 27535533). 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. (PMID 23335809, internal laboratory contributor SCV000617324.2)
Met criteria codes
PS3
Han, SY et al. evaluated the phosphatase activity of this variant and demonstrated that activity was similar to null (figure 2C). Figure 4 from this paper evaluated PTEN binding activity to LMVs (*review with group, unsure of interpretation of this blot). This variant is described as being at the walls of the phosphatase domain (residues 160-168). All mutations within the active site pocket illuminated phosphatase activity. Waite KA et al. reported null phosphatase activity for this variant (Table 1). Myers et al demonstrated a dramatic decrease in activity of phosphatase found in tumor samples (Figure 5).
Miguell et al. lists variant as having a G score of -4.228052892 which is in the truncation-like range (<2.13). PubMed:29706350
PS2
GeneDx internal case of male child with extreme macrocephaly and developmental delay. De novo occurrence confirmed via exome.
PM2
absent gnomAD
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4_Supporting
Pilarski et al. reviewed molecular and clinical data on 802 patients referred for PTEN analysis by a single lab. This variant was reported in one patient. No individual clinical information was provided in this paper. Banneau G et al. reported PTEN mutations found in patients with breast cancer. Table S1 in additional file 1 provided clinical information on one patient, age 59, with invasive lobular cancer and was stated to have Cowden. No further details were provided (table 2).Tan MH et al established a clinical scoring system of patient for PTEN mutation testing and identified two patients with this variant (listed in supplemental table S2, individuals 46 and 165). *consider asking for more detailed clinical data. Bubien et al. , supplemental table lists individual 17 as having mucocutaneous lesions, benign thyroid condition, LDD and macrocephaly. Internal data from Ambry: 1. male patient in his 30's with hamartomatous polyps in her 20's, lipomas and neuromas (CC score = 17) and 2., male patient in his 20's with thyroid ca, facial papules and HC = 59cm (CC score = 16). GeneDx internal case: male child with extreme macrocephaly (+5SD) and developmental delay and confirmed de novo via exome. Proband specificity score = 1.
PubMed:23335809
Not Met criteria codes
PS1
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
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
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
PVS1
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
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
Curation History
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