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_000314.8(PTEN):c.1061C>A (p.Pro354Gln)

CA000275

143020 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: e75a40b0-8e18-418e-b6c7-079646958d18
Approved on: 2023-06-14
Published on: 2023-10-19

HGVS expressions

NM_000314.8:c.1061C>A
NM_000314.8(PTEN):c.1061C>A (p.Pro354Gln)
NC_000010.11:g.87965321C>A
CM000672.2:g.87965321C>A
NC_000010.10:g.89725078C>A
CM000672.1:g.89725078C>A
NC_000010.9:g.89715058C>A
NG_007466.2:g.106883C>A
ENST00000686459.1:c.*647C>A
ENST00000688158.1:c.*1172C>A
ENST00000688308.1:c.1061C>A
ENST00000688922.1:c.982C>A
ENST00000693560.1:c.1580C>A
ENST00000371953.8:c.1061C>A
ENST00000371953.7:c.1061C>A
NM_000314.5:c.1061C>A
NM_000314.6:c.1061C>A
NM_001304717.2:c.1580C>A
NM_001304718.1:c.470C>A
NM_000314.7:c.1061C>A
NM_001304717.5:c.1580C>A
NM_001304718.2:c.470C>A
More

Likely Benign

Met criteria codes 4
PP2 BS1 BP4 BS3_Supporting
Not Met criteria codes 22
PP4 PP1 PP3 PM6 PM2 PM3 PM1 PM4 PM5 PVS1 BA1 BS2 BS4 BP5 BP7 BP2 BP3 BP1 PS2 PS4 PS3 PS1

Evidence Links 7

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.1061C>A (p.Pro354Gln) variant meets criteria to be classified as likely benign 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). BS1: To be applied for variants with filtering allele frequency (FAF) of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. Popmax FAF of this variant=0.0001051. BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function. This variant: score of 0.09 (WT-like range) on high throughput phosphatase assay (PMID:29706350). BP4: REVEL score < 0.5 (score=0.497). 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. Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign strong and 2 benign supporting = -6. 1 pathogenic supporting = 1. Total = – 5 (likely benign).
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.
BS1
gnomAD v2.1.1: 19/125384 (.0115%) European/non-Finnish pop (.00011515). Popmax Filtering AF is .0001051 which meets BS1 criteria [gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)].
BP4
REVEL score < 0.5 (score=0.497)
BS3_Supporting
In vitro or in vivo functional study or studies showing no damaging effect on protein function. Score of 0.09 (WT-like range) on high throughput phosphatase assay (PMID:29706350).
WT-like abundance on high-throughput VAMP-seq assay, indicating stable protein PubMed:29785012
Score of 0.09 (WT-like range) on high throughput phosphatase assay PubMed:29706350
Not Met criteria codes
PP4
Eng lab paper, same pts in other lab publications. Identified in two sisters. The first being a 49 year old woman with normal head circumference and a history of breast cancer, fibrocystic breast disease and uterine fibroids. Reported to NOT meet ICC criteria. The second being a 56 year old female (head circumference unknown) with a history of fibrocystic breast disease and a genitourinary tumor. This patient also did NOT meet ICC criteria. PubMed:21343951
Identified in a pt undergoing clinical testing; no phenotype info provided. PubMed:21659347
Germline finding in a pt with neuroblastoma PubMed:26580448
Identified in a pt with BrCA dx 57 who had a FDR with BrCA. PubMed:26898890
Seen in a pt with a Lynch-related cancer and/or polyps who also harbored an MSH2 PATH, but no phenotype provided. PubMed:25980754
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
0.015% (19/122,896) European (Non-Finnish) alleles in gnomAD; 3/1886 alleles in GME variome.
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
BA1
0.015% (19/122,896) European (Non-Finnish) alleles in gnomAD; 3/1886 alleles in GME variome.
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
BP5
Some cases suggestive, but overlapping phenotypes with PHTS
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
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
Curation History
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