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.104T>G (p.Met35Arg)

CA000268

7825 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2374c339-e2d7-4496-9d9a-d33c1abd8dce
Approved on: 2018-07-25
Published on: 2019-07-23

HGVS expressions

NM_000314.6:c.104T>G
NM_000314.6(PTEN):c.104T>G (p.Met35Arg)
NC_000010.11:g.87894049T>G
CM000672.2:g.87894049T>G
NC_000010.10:g.89653806T>G
CM000672.1:g.89653806T>G
NC_000010.9:g.89643786T>G
NG_007466.2:g.35611T>G
NM_000314.5:c.104T>G
NM_001304717.2:c.623T>G
NM_001304718.1:c.-602T>G
NM_000314.7:c.104T>G
NM_001304717.5:c.623T>G
NM_001304718.2:c.-602T>G
ENST00000371953.7:c.104T>G
ENST00000462694.1:n.106T>G
ENST00000610634.1:c.2T>G
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Pathogenic

Met criteria codes 4
PS3 PS2 PP2 PM2
Not Met criteria codes 18
PVS1 BA1 BS1 BS3 BS4 BS2 BP7 BP5 BP4 BP2 PS1 PS4 PP3 PP1 PM5 PM4 PM1 PM6

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
PTEN VCEP
PTEN c.104T>G (p.Met35Arg) 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. (PMID 9425889) PS3: Phosphatase activity <50% of wild type. (PMID 21828076, 25875300) 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.
Met criteria codes
PS3
I agree (FH)
Figure 2: functional analysis of PTEN tumor suppressor function in vivo on a panel of N-terminal PTEN mutations including M35R. Shown in 2B, 2C and table 1, there is increased nuclear localization on a PTEN WT background when tested on mammalian COS-7 cells. A partial inhibition of nuclear accumulation was observed on a PTEN 1-375 background. PIP3 phosphatase activity was assessed next using S. cerevisiae heterologous reconstitution system. Fig 2D, 2E, Table 2, M35R totally abrogated PTEN activity in the yeast model. Figure 2D shows no galactose activity indicating non-functioning PTEN. PubMed:25875300
Figure 6(A) demonstrates functional assessment of PTEN mutations in relation to PHTS hereditary syndromes. M35R shows approx 95% PIP3 positive cells and shows WT at 0%. Evidence of inhibited dephosphorylation. Might be useful to look at supplementary data (table S1). I could not find the supplementary table. PubMed:21828076
PS2
Per Olschwang S et al, the genotypes at 8 highly polymorphic microsatellite loci in the parents and patient confirmed mendelian inheritance. Sequencing of exon 2 amplified from the DNAs of both parents revealed only codon 35 for methionine, demonstrating that codon 35 of arginine was a de novo mutation (FH). Per Expert Panel review, PS2 applies as opposed to PM6 (JM).
Parents of patient with variant were tested and did not have variant. No proof of paternity documented/mentioned. PubMed:9425889
PP2
I Agree (FH)
PM2
variant not in gnomAD or other databases (MP) Per Felicia, I agree
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
variant not in gnomAD or other databases (MP) Per Felicia, I agree
BS1
variant not in gnomAD or other databases (MP) Per Felicia, I agree
BS3
I agree (FH)
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
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
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
PM6
Parents of patient G710 were negative for variant. I disagree with PM6 (FH)
Parents of patient with variant were tested and did not have variant. No proof of paternity documented/mentioned. PubMed:9425889
Curation History
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