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]
Link to SEPIO compliant JSON-LD document

Variant: NM_000314.6(PTEN):c.740T>C (p.Leu247Ser)

CA16044135

223142 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 33e47859-5909-4f34-ac6c-c5bf41ab8544
Approved on: 2023-08-04
Published on: 2023-10-19

HGVS expressions

NM_000314.6:c.740T>C
NM_000314.6(PTEN):c.740T>C (p.Leu247Ser)
NC_000010.11:g.87957958T>C
CM000672.2:g.87957958T>C
NC_000010.10:g.89717715T>C
CM000672.1:g.89717715T>C
NC_000010.9:g.89707695T>C
NG_007466.2:g.99520T>C
ENST00000686459.1:c.*326T>C
ENST00000688158.1:c.*851T>C
ENST00000688308.1:c.740T>C
ENST00000688922.1:c.661T>C
ENST00000693560.1:c.1259T>C
ENST00000371953.8:c.740T>C
ENST00000371953.7:c.740T>C
ENST00000472832.2:c.167T>C
NM_000314.5:c.740T>C
NM_001304717.2:c.1259T>C
NM_001304718.1:c.149T>C
NM_000314.7:c.740T>C
NM_001304717.5:c.1259T>C
NM_001304718.2:c.149T>C
NM_000314.8:c.740T>C
NM_000314.8(PTEN):c.740T>C (p.Leu247Ser)

Likely Pathogenic

Met criteria codes 5
PM6_Strong PM2_Supporting PP3 PP2 PS3_Moderate
Not Met criteria codes 21
BS3 BS1 BS4 BS2 BP7 BP5 BP3 BP4 BP1 BP2 PVS1 PS2 PS1 PS4 PP4 PP1 PM1 PM4 PM5 PM3 BA1

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 3.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
PTEN VCEP
PTEN c.740T>C (p.Leu247Ser) 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 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM2_Supporting: Absent in large sequenced populations (PMID: 27535533). PM6_Strong: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (PMIDs: 28086757 and 29752200) 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. PS3_Moderate: Functional studies showing a damaging effect on protein function. Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350). This variant: score of -1.669765892. PP3: REVEL score > 0.7 (this variant: score=0.918).
Met criteria codes
PM6_Strong
Negishi et al reported that patient #5 had variant as confirmed de novo event (PMID: 28086757; Please note: Kato et al reported the same patient in PMID: 29752200). Added the upweight to PM6_Strong due to the 4.9mo female who had an OFC of 4.3 SD and developmental delay. Proband specificity score is 5.
PM2_Supporting
Variant not found in gnomAD.
PP3
REVEL score of 0.918 (>0.7)
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.
PS3_Moderate
Per new PTEN VCEP guidelines, PS3_M can be applied for functional scores in the hypomorphic range in Mighell et al. 2018.
Not Met criteria codes
BS3
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
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
BP3
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
BP1
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
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
PS4
Proband specificity score of 5 for child = 1 point. PS4 weight was removed here and combined with PM6 to upweight to PM6_Strong. See PM6_Strong.
Per M. Perpich: Patient #5 described in paper by Negishi et al is a 4.9mo female who has an OFC of 4.3 SD and developmental delay. Proband specificity score is 5 so PP4 can be applied. PubMed:28086757
PP4
Patient #5 described in paper by Negishi et al is a 4.9mo female who has an OFC of 4.3 SD and developmental delay. Proband specificity score is 5 so PP4 can be applied. - JM agree but added to PS4 instead of PP4.
Patient #5 proband specificity score is 5. PubMed:28086757
PP1
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
PM4
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
PM3
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
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