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]

Variant: NM_000314.6(PTEN):c.701G>A (p.Arg234Gln)

CA000551

7840 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 5fe899fa-c13c-4145-9397-0b200e380e4c
Approved on: 2023-06-14
Published on: 2023-10-19

HGVS expressions

NM_000314.6:c.701G>A
NM_000314.6(PTEN):c.701G>A (p.Arg234Gln)
NC_000010.11:g.87957919G>A
CM000672.2:g.87957919G>A
NC_000010.10:g.89717676G>A
CM000672.1:g.89717676G>A
NC_000010.9:g.89707656G>A
NG_007466.2:g.99481G>A
ENST00000686459.1:c.*287G>A
ENST00000688158.1:c.*812G>A
ENST00000688308.1:c.701G>A
ENST00000688922.1:c.622G>A
ENST00000693560.1:c.1220G>A
ENST00000371953.8:c.701G>A
ENST00000371953.7:c.701G>A
ENST00000472832.2:c.128G>A
NM_000314.5:c.701G>A
NM_001304717.2:c.1220G>A
NM_001304718.1:c.110G>A
NM_000314.7:c.701G>A
NM_001304717.5:c.1220G>A
NM_001304718.2:c.110G>A
NM_000314.8:c.701G>A
NM_000314.8(PTEN):c.701G>A (p.Arg234Gln)
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Uncertain Significance

Met criteria codes 2
PP2 PM2_Supporting
Not Met criteria codes 24
PS4 PS2 PS3 PS1 BA1 PM3 PM1 PM4 PM5 PVS1 PM6 PP1 PP4 PP3 BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP1 BP4

Evidence Links 4

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
NM_000314.8(PTEN):c.701G>A (p.Arg234Gln) is currently classified as a variant of uncertain significance 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 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.
Met criteria codes
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.
PM2_Supporting
Absent in large sequenced populations in the gnomAD cohort. (PMID 27535533).
Not Met criteria codes
PS4
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
PS3
Need to discuss PS3_supporting with group, may not apply? Matreyek et al (no PMID yet) also describe variant as PATH in ClinVar (is actually conflicting) but with normal protein abundance. Eng lab papers also describe M3/M4 mouse with this plus 4 other PTEN missense variants; can't use for analyzing function of this variant separately. I agree with PS3_supporting for Staal et al. (FH) Following expert panel discussion, group decided to apply no criteria based on conflicting nature of functional results.
“WT-like” range for phosphatase activity (score -0.8, WT-like range between -1.11 and 0.89) PubMed:29706350
Variant transfected into U87MG glioma cell line (PTEN-null). Cells with mutant had 5x higher proliferation rate than WT over 2 week period and demonstrated apoptosis rate comparable to empty vector (WT had 2x rate). Mutant also had increased PKB phosphorylation. PubMed:12085208
“WT-like” protein abundance on high throughput assay PubMed:29785012
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
I agree (FH)
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
PVS1
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No GDx internal cases with phenotype specificity. No Ambry internal cases with phenotype specificity (FH).
Germline finding in a male pt with R frontal meningioma dx 42, L frontal low-grade glioma dx 47, this tumor turned into an anaplastic oligodendroglioma when resected at 50 yrs. This tumor recurred a few yrs later. Pt had no prev unusual med hx. Tumors also had variant and no LOH at 10q. PubMed:12085208
Germline finding in an 82yo Japanese woman with panc CA dx 82 (no LOH in tumor). Fam hx brother with gastric cancer dx 60 and sister with ovarian cancer dx 60. Workup negative for macrocephaly, skin/mucosal papillomas, thyroid/uterine/breast disease. PubMed:28755079
PP3
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
BS3
Need to discuss PS3_supporting with group, may not apply? Matreyek et al (no PMID yet) also describe variant as PATH in ClinVar (is actually conflicting) but with normal protein abundance. Eng lab papers also describe M3/M4 mouse with this plus 4 other PTEN missense variants; can't use for analyzing function of this variant separately. I agree with PS3_supporting for Staal et al. (FH)
“WT-like” range for phosphatase activity (score -0.8, WT-like range between -1.11 and 0.89) PubMed:29706350
Variant transfected into U87MG glioma cell line (PTEN-null). Cells with mutant had 5x higher proliferation rate than WT over 2 week period and demonstrated apoptosis rate comparable to empty vector (WT had 2x rate). Mutant also had increased PKB phosphorylation. PubMed:12085208
“WT-like” protein abundance on high throughput assay PubMed:29785012
BS1
I agree (FH)
BS2
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
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
BP1
I agree (FH)
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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