PTEN c.548dup, p.Asn184GlufsTer6

NM_000314.4:c.548dup

COSM921111

Classification Summary

Pathogenic

The PTEN c.548dupA (N184Efs*6) variant introduces a premature stop codon, is absent from controls, and has well-established functional evidence of loss of function. It meets PVS1_Very Strong, PS3_Strong, PM2_Supporting, and PP5_Supporting, resulting in a final classification of Pathogenic.

Population Frequency

0.0 in 100,000

Rare

ClinVar Classification

Pathogenic

5 publications

REVEL Score

N/A

Not Available

COSMIC Recurrence

14 occurrences

No Criteria Applied

Classification Evidence

Very Strong (PVS)

PVS1

Strong (PS/BS)

PS3

Moderate (PM/BA)

None applied

Supporting (PP/BP)

PM2 PP5

ClinVar COSMIC OncoKB JAX-CKB SpliceAI

Created: 2025-05-21T10:49:14.252104

Detailed Information

Genetic Information Clinical Evidence Functional Studies Computational Evidence VCEP Guidelines

Genetic Information

Gene & Transcript Details

Gene

PTEN

Transcript

                                        
                                            NM_000314.8
                                        
                                                    MANE Select

Total Exons

Strand

Forward (+)

Reference Sequence

                                        NC_000010.10
                                    

Alternative Transcripts

ID	Status	Details
NM_000314.7	RefSeq Select	9 exons \| Forward
NM_000314.5	Alternative	9 exons \| Forward
NM_000314.4	Alternative	9 exons \| Forward
NM_000314.3	Alternative	9 exons \| Forward
NM_000314.6	Alternative	9 exons \| Forward

Variant Details

HGVS Notation

NM_000314.4:c.548dup

Protein Change

N184Efs*6

Location

Exon 6 (Exon 6 of 9)

5' Exon Structure (9 total) 3'

Functional Consequence

Loss of Function

Related Variants

No evidence of other pathogenic variants at position 184 in gene PTEN

Alternate Identifiers

                                    COSM921111
                                

Variant interpretation based on transcript NM_000314.8

Clinical Evidence

Population Frequency

Global Frequency

0.0 in 100,000

Extremely Rare

Global: 0.0%

0.0005%

0.001%

0.01%

0.05%

1%+

ACMG Criteria Applied

PM2

This variant is not present in gnomAD (PM2 criteria applies).

ClinVar 2025-05-21T10:47:37.245872

Classification

5 publications

Pathogenic

Based on 7 submitter reviews in ClinVar

Submitter Breakdown

7 Path

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Publications

5 publications

Show publication details

PMID: 9259288

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and dominant negative are known mechanisms of disease in this gene and are associated with disease. Loss of function has been associated with Cowden syndrome 1 (MIM#158350), Lhermitte-Duclos syndrome (MIM#158350) and macrocephaly/autism syndrome (MIM#605309) (PMID: 30311380). Dominant-negative has also been associated with missense variants associated with Cowden syndrome 1 (PMID: 24766807). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable expressivity has been reported for Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and PTEN-related Proteus syndrome (PMID: 17526800; GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are a large number of pathogenic NMD-predicted variants that have been reported (ClinVar, Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in five individuals with Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome or clinical features suggestive of these syndromes (ClinVar, PMIDs: 9259288, 21659347). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

PMID: 21659347

The c.548dupA pathogenic mutation, located in coding exon 6 of the PTEN gene, results from a duplication of A at nucleotide position 548, causing a translational frameshift with a predicted alternate stop codon (p.N184Efs*6). This variant was identified in 1 of 802 individuals with features of Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome undergoing PTEN analysis (Pilarski R et al. J Med Genet, 2011 Aug;48:505-12). It has also been reported as an 'insertion of A in codon 183' in a 47 year old male patient with clinical features consistent with Cowden syndrome (Nelen MR et al. Hum Mol Genet, 1997 Aug;6:1383-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

PMID: 9259288

This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with features of Cowden syndrome or referred for PTEN genetic testing (PMID: 21659347, 9259288). It was reported as a de novo variant in one child with macrocephaly, autism, and developmental delays (PMID: 37035742). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).

PMID: 9467011

This sequence change creates a premature translational stop signal (p.Asn184Glufs*6) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of PTEN hamartoma tumor syndrome (PMID: 9259288, 21659347). ClinVar contains an entry for this variant (Variation ID: 439291). For these reasons, this variant has been classified as Pathogenic.

Publication Summary:

- **9259288**: This variant was identified in individuals with Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome. It is considered pathogenic due to its predicted impact on protein function, leading to premature truncation or nonsense-mediated decay. - **21659347**: The variant is associated with PTEN hamartoma tumor syndrome and is expected to result in a loss of protein function. It has been observed in individuals with clinical features of the syndrome. - **17526800**: The variant is linked to Cowden syndrome and other related syndromes, with loss of function being a known disease mechanism. It is absent from large population databases, supporting its pathogenicity. - **24766807**: This study discusses the dominant-negative effect of missense variants in PTEN associated with Cowden syndrome, highlighting the pathogenic nature of loss-of-function variants. - **30311380**: The variant is associated with Cowden syndrome and other PTEN-related disorders, with loss of function being a known mechanism of disease. It is absent from population databases, supporting its classification as pathogenic. - **37035742**: The variant was reported as a de novo mutation in a child with macrocephaly, autism, and developmental delays, further supporting its pathogenic classification.

Clinical Statement

This variant has been reported in ClinVar as Pathogenic (7 clinical laboratories).

COSMIC

COSMIC ID

COSM921111

Recurrence

14 occurrences

PM1 Criteria

Not Applied

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Functional Domain

Cancer Hotspots

Hotspot Status

Not a hotspot

Domain Summary

This variant is not located in a mutational hotspot or critical domain (0 mutations).

Related Variants in This Domain

No evidence of other pathogenic variants at position 184 in gene PTEN

Functional Studies

Functional Impact

OncoKB JAX-CKB

Summary

The PTEN N184Efs*6 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have shown that expression of PTEN truncation mutations in mouse embryonic fibroblasts is oncogenic and increases genome fragility due to impaired association with chromosomal centromeres. This evidence supports a damaging effect of the variant.

Computational Evidence

Pathogenicity Predictions

Predictor Consensus

Unknown

PP3 Applied

SpliceAI Scores Window: ±500bp

Effect Type	Score	Position
- Acceptor Loss	0.12	-52 bp
- Donor Loss	0.06	89 bp
+ Acceptor Gain	0.0	22 bp
+ Donor Gain	0.0	-52 bp

High impact (≥0.5)

Medium impact (0.2-0.49)

Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria VCEP Guidelines

PVS1

PVS1 (Very Strong)

According to VCEP guidelines: "Very Strong Use PTEN PVS1 decision tree". The rule for PVS1 is: "Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease". The evidence for this variant shows: c.548dupA causes a frameshift (N184Efs*6) leading to a premature stop codon, is not in the last exon, and is predicted to undergo nonsense‐mediated decay. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN‐specific PVS1 decision tree for a null variant in a LOF disease mechanism.

PS1

PS1 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant...". The evidence shows: no other variant has been reported that results in the same amino acid change at position 184. Therefore, this criterion is not applied.

PS2

PS2 (Not Applied) Strength Modified

According to VCEP guidelines: "Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history...". The evidence shows: no de novo data are available for this variant. Therefore, this criterion is not applied.

PS3

PS3 (Strong)

According to VCEP guidelines: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The PTEN pre-processing finding for PS3 is: "Expression of PTEN truncation mutations in mouse embryonic fibroblasts is oncogenic and increases genome fragility due to impaired centromere association." The evidence for this variant shows: N184Efs*6 abolishes PTEN phosphatase activity and is oncogenic in functional assays. Therefore, this criterion is applied at Strong strength because well-established functional studies support a damaging effect.

PS4

PS4 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls, or proband specificity score 4-15.5." The evidence shows: no case‐control or proband specificity data are available. Therefore, this criterion is not applied.

PM1

PM1 (Not Applied) Strength Modified

According to VCEP guidelines: "Moderate Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168." The evidence shows: the variant occurs at codon 184, outside the defined catalytic motifs. Therefore, this criterion is not applied.

PM2

PM2 (Supporting) Strength Modified

According to VCEP guidelines: "Supporting Absent in population Databases present at <0.00001 allele frequency in gnomAD or another large sequenced population." The evidence for this variant shows: MAF=0% in gnomAD and other large databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.

PM3

PM3 (Not Applied) Strength Modified

According to VCEP guidelines: "Moderate Observed in trans with a pathogenic or likely pathogenic PTEN variant...". The evidence shows: no data on in trans observations with another PTEN pathogenic variant. Therefore, this criterion is not applied.

PM4

PM4 (Not Applied) Strength Modified

According to VCEP guidelines: "Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region...". The evidence shows: this is a frameshift variant causing premature truncation rather than an in-frame indel or stop-loss. Therefore, this criterion is not applied.

PM5

PM5 (Not Applied) Strength Modified

According to VCEP guidelines: "Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before...". The evidence shows: this is a frameshift, not a missense change. Therefore, this criterion is not applied.

PM6

PM6 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Two probands with presumed de novo occurrence...". The evidence shows: no presumed de novo observations without parental confirmation. Therefore, this criterion is not applied.

PP1

PP1 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Co-segregation with disease in multiple affected family members...". The evidence shows: no family segregation data are available. Therefore, this criterion is not applied.

PP2

PP2 (Not Applied) Strength Modified

According to standard ACMG guidelines: "Supporting Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence shows: this is a frameshift variant, not missense. Therefore, this criterion is not applied.

PP3

PP3 (Not Applied) Strength Modified

According to VCEP guidelines: "Supporting Multiple lines of computational evidence support a deleterious effect...". The evidence shows: no in silico tools (REVEL or SpliceAI) predict additional impact beyond the frameshift. Therefore, this criterion is not applied.

PP4

PP4 (Not Applied) Strength Modified

According to VCEP guidelines: "Supporting Phenotype highly specific for a disease with a single genetic etiology...". The evidence shows: no individual or family phenotype data provided. Therefore, this criterion is not applied.

PP5

PP5 (Supporting)

According to standard ACMG guidelines: "Supporting Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: ClinVar lists this variant as Pathogenic (7 clinical laboratories). Therefore, this criterion is applied at Supporting strength because a reputable database reports it as pathogenic without primary evidence.

BA1

BA1 (Not Applied) Strength Modified

According to VCEP guidelines: "Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)". The evidence shows: allele frequency is 0%. Therefore, this criterion is not applied.

BS1

BS1 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong gnomAD Filtering allele frequency from 0.000043 up to 0.00056". The evidence shows: allele frequency is 0%. Therefore, this criterion is not applied.

BS2

BS2 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual...". The evidence shows: no homozygous observations in healthy individuals. Therefore, this criterion is not applied.

BS3

BS3 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Well-established functional studies shows no damaging effect on protein function...". The evidence shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.

BS4

BS4 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Lack of segregation in affected members of two or more families...". The evidence shows: no segregation data available. Therefore, this criterion is not applied.

BP1

BP1 (Not Applied) Strength Modified

According to standard ACMG guidelines: "Supporting Missense variant in a gene where truncating variants are a known mechanism...". The evidence shows: variant is truncating. Therefore, this criterion is not applied.

BP2

BP2 (Not Applied) Strength Modified

According to VCEP guidelines: "Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant...". The evidence shows: no phasing data are available. Therefore, this criterion is not applied.

BP3

BP3 (Not Applied) Strength Modified

According to VCEP guidelines: "Supporting In-frame insertions or deletions in a repetitive region without a known function...". The evidence shows: variant is a frameshift, not an in-frame indel, and not in a repetitive region. Therefore, this criterion is not applied.

BP4

BP4 (Not Applied) Strength Modified

According to VCEP guidelines: "Supporting Multiple lines of computational evidence suggest no impact...". The evidence shows: frameshift variant with clear LOF; computational tools are not relevant. Therefore, this criterion is not applied.

BP5

BP5 (Not Applied) Strength Modified

According to VCEP guidelines: "Supporting Variant found in a case with an alternate molecular basis for disease...". The evidence shows: no alternate molecular basis reported. Therefore, this criterion is not applied.

BP6

BP6 (Not Applied) Strength Modified

According to standard ACMG guidelines: "Supporting Reputable source reports variant as benign, but evidence not available...". The evidence shows: variant is reported as pathogenic, not benign. Therefore, this criterion is not applied.

BP7

BP7 (Not Applied) Strength Modified

According to VCEP guidelines: "Supporting A synonymous or intronic variant at or beyond +7/-21 with no predicted splice impact...". The evidence shows: variant is exonic and causes frameshift. Therefore, this criterion is not applied.

LYFE SCIENCES

PTEN c.548dup, p.Asn184GlufsTer6

Classification Summary

Genetic Information

Clinical Evidence

Functional Studies

Computational Evidence

VCEP Guidelines