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_000314.7(PTEN):c.838A>G (p.Ile280Val)

CA377485551

468719 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d625033c-bcc2-4e6c-ad5d-f0259d0cf8d7
Approved on: 2020-10-20
Published on: 2022-09-30

HGVS expressions

NM_000314.7:c.838A>G
NM_000314.7(PTEN):c.838A>G (p.Ile280Val)
NC_000010.11:g.87960930A>G
CM000672.2:g.87960930A>G
NC_000010.10:g.89720687A>G
CM000672.1:g.89720687A>G
NC_000010.9:g.89710667A>G
NG_007466.2:g.102492A>G
ENST00000686459.1:c.*424A>G
ENST00000688158.1:c.*949A>G
ENST00000688308.1:c.838A>G
ENST00000688922.1:n.759A>G
ENST00000693560.1:c.1357A>G
ENST00000371953.8:c.838A>G
ENST00000371953.7:c.838A>G
ENST00000472832.2:n.265A>G
NM_000314.5:c.838A>G
NM_000314.6:c.838A>G
NM_001304717.2:c.1357A>G
NM_001304718.1:c.247A>G
NM_001304717.5:c.1357A>G
NM_001304718.2:c.247A>G
NM_000314.8:c.838A>G
NM_000314.8(PTEN):c.838A>G (p.Ile280Val)

Uncertain Significance

Met criteria codes 3
BS3 PM2 PP2
Not Met criteria codes 23
PVS1 BS2 BS4 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PM6 PM3 PM1 PM4 PM5 PS2 PS4 PS3 PS1 BA1 PP4 PP1 PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
PTEN VCEP
PTEN c.838A>G (p.Ile280Val) is currently classified as a variant of uncertain significance 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). PM2: present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (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. BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 29706350, PMID 29785012)
Met criteria codes
BS3
Matreyek at al. lists variant as having a cumulative score of 1.012413 which is in the WT-like range. Miguell et al. lists variant as -0.063958094 which is in the WT-like range meeting BS3/BS3_supporting)
PM2
Allele frequency reported: 1/112924 in Finnish ancestry in gnomAD and 1/249790 in total population, or <0.00001 (0.001%) allele frequency.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Not Met criteria codes
PVS1
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
BS4
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
BP2
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
BP5
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
PM6
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
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Gene Dx internal case: proband Cauc M child with hypotonia, macrocephaly +3SD, motor delay, no GU exam. Mom POSITIVE, has asthma and hypoglycemia, she has a mat half-brother with RCC dx 30s but no other cancers. Ped proband specificity score = 4 only (no point).
PS3
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
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
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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