PTENc.63C>TUncertain significance

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Variant interpretation report

PTEN c.63C>T, p.(Phe21=)

NM_000314.8:c.63C>T NP_000305.3:p.(Phe21=) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About PTEN

No gene-level summary was recorded for this case.

Key facts

Condition: PTEN hamartoma tumor syndrome
Inheritance: Autosomal dominant
Evidence used: 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: ClinGen PTEN VCEP v3.2
Other laboratories (ClinVar): 3 Likely benign · 1 Benign
Pipeline record: 21 Aug 2026 · version 7.0.6

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): The variant is essentially absent from population databases (gnomAD v4.1 allele frequency 6.2e-7; 1/1,614,140 alleles, 0 homozygotes), below the PTEN VCEP PM2_Supporting threshold of 0.001%.
BP7 (supporting): Synonymous variant located outside the splice consensus region (c.63 in exon 1, 16 bp upstream of the exon 1 donor) with SpliceAI predicting no impact on splicing (max delta 0.116), meeting BP7 at supporting level.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is ClinGen PTEN VCEP v3.2. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

The variant is essentially absent from population databases (gnomAD v4.1 allele frequency 6.2e-7; 1/1,614,140 alleles, 0 homozygotes), below the PTEN VCEP PM2_Supporting threshold of 0.001%.

Benign criteria applied · 1

BP7Supporting

BP7 · supporting

Synonymous variant located outside the splice consensus region (c.63 in exon 1, 16 bp upstream of the exon 1 donor) with SpliceAI predicting no impact on splicing (max delta 0.116), meeting BP7 at supporting level.

Recorded classification: Uncertain significance

ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, BP7 supporting benign; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

1 / 1,614,140 alleles

gnomAD v4.1: 1 / 1,614,140 alleles. Recorded AF 6.19525e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.116 maximum delta

Recorded SpliceAI maximum delta score: 0.116. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP7 → SpliceAI ↗

ClinVar submissions

4 reported laboratory submissions

3 Likely benign · 1 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen PTEN VCEP v3.2, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 15 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000314.8:c.63C>T is a synonymous substitution (NP_000305.3:p.Phe21=) in PTEN exon 1 that does not alter the encoded amino acid sequence.

SpliceAI predicts no significant splicing impact (max delta score 0.116), supporting BP7 at supporting strength for a synonymous variant located outside the splice consensus region.

The variant is essentially absent from population databases (gnomAD v4.1 allele frequency 6.2e-7, 1/1,614,140 alleles, 0 homozygotes), meeting PM2 at supporting strength.

ClinVar reports the variant as Likely benign (3 submitters) and Benign (1 submitter) under a single-submitter, non-expert-panel review status; PP5 and BP6 are not applicable under the PTEN VCEP.

With only PM2_Supporting and BP7 met and no strong or moderate criteria satisfied, the variant is classified as a Variant of Uncertain Significance.

Met · 2

PM2 SupportingThe variant is essentially absent from population databases (gnomAD v4.1 allele frequency 6.2e-7; 1/1,614,140 alleles, 0 homozygotes), below the PTEN VCEP PM2_Supporting threshold of 0.001%. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF 6.2e-7 (1/1
614
140 alleles)
absent from gnomAD v2.1 and gnomAD-Canada

Sources

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

BP7 SupportingSynonymous variant located outside the splice consensus region (c.63 in exon 1, 16 bp upstream of the exon 1 donor) with SpliceAI predicting no impact on splicing (max delta 0.116), meeting BP7 at supporting level. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.116 (no predicted splice impact)
synonymous variant outside +7/-21 splice region

Sources

spliceai ↗cspec ↗

Not met · 15 · evaluated, threshold not reached

PS2 No de novo (maternity and paternity confirmed) observation of this variant has been reported. Details ▾Hide ▴

Still missing

No de novo observation reported

PS3 No RNA, mini-gene, or other splicing assay demonstrates a damaging effect, and the variant is synonymous and absent from the Mighell et al. missense saturation mutagenesis dataset (mmc2.xlsx covers missense variants only). Details ▾Hide ▴

Evidence considered

SpliceAI predicts no splicing impact
no variant-specific functional assay
mmc2.xlsx is missense-only

Still missing

No variant-specific functional assay

Sources

vcep_mmc2

PS4 No proband specificity score, case-control prevalence data, or variant-specific proband observations are available. Details ▾Hide ▴

Still missing

No proband case data

PM1 Residue 21 lies outside the PTEN catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168), and the synonymous change does not alter these domains. Details ▾Hide ▴

Evidence considered

Residue 21 is not within catalytic motifs 90-94
123-130
or 166-168

Sources

cspec ↗

PM6 No assumed de novo observation of this variant has been reported. Details ▾Hide ▴

Still missing

No assumed de novo observation reported

PP1 No co-segregation data in affected family members are available. Details ▾Hide ▴

Still missing

No segregation data

PP3 SpliceAI (max delta 0.116) predicts no splicing impact, and REVEL/BayesDel are not applicable to a synonymous variant; no concordant computational evidence of a deleterious effect is present. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.116 (no predicted splicing impact)

Sources

spliceai ↗

BA1 gnomAD filtering allele frequency (6.2e-7) is far below the BA1 stand-alone threshold (>0.056%). Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF 6.2e-7

Sources

gnomad_v4 ↗

BS1 gnomAD allele frequency (6.2e-7) is below the BS1_Supporting threshold (>=0.00043%). Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF 6.2e-7

Sources

gnomad_v4 ↗

BS2 No homozygous observation in healthy or PHTS-unaffected individuals (gnomAD homozygote count = 0). Details ▾Hide ▴

Evidence considered

gnomAD v4.1 homozygotes = 0

Sources

gnomad_v4 ↗

BS3 No RNA, mini-gene, or other splicing assay demonstrates absence of splicing impact; computational prediction alone does not satisfy BS3. Details ▾Hide ▴

Still missing

No functional splicing assay data

BS4 No family data demonstrate lack of segregation with disease. Details ▾Hide ▴

Still missing

No segregation data

BP2 No observation in trans with a pathogenic/likely pathogenic PTEN variant, nor three observations in cis or phase-unknown with different pathogenic/likely pathogenic PTEN variants. Details ▾Hide ▴

Still missing

No phase information with a pathogenic PTEN variant

BP4 SpliceAI (max delta 0.116) is within the benign range (0-0.2), but the PTEN VCEP BP4 rule requires concordance of SpliceAI AND VarSeak; VarSeak data are unavailable. BP7 is applied instead to avoid double-counting. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.116 (benign range)
VarSeak not available

Still missing

VarSeak splice prediction not available for concordance

Sources

spliceai ↗cspec ↗

BP5 No case with an alternate molecular basis for disease has been reported. Details ▾Hide ▴

Still missing

No alternate-molecular-basis case data

Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANM_000314.8:c.63C>T is a synonymous substitution (p.Phe21=) and does not create a null allele (nonsense, frameshift, canonical splice, or initiation-codon variant), so the PTEN PVS1 decision tree does not apply. Details ▾Hide ▴

Evidence considered

Synonymous variant p.Phe21=
not a null variant

Sources

pvs1_variant_assessmentpvs1_gene_context

PS1 N/AA synonymous change does not alter the amino acid, so there is no established pathogenic variant with the same amino acid change, and no established pathogenic splicing variant occurs at this nucleotide position. Details ▾Hide ▴

Evidence considered

No amino acid change
no pathogenic splicing comparator at this position

PM3 VCEPRecessive trans-phase criterion; PTEN is autosomal dominant and PM3 is Not Applicable per the VCEP. Details ▾Hide ▴

Sources

cspec ↗

PM4 N/AProtein-length-change (in-frame indel / stop-loss) criterion; not applicable to a synonymous substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AThe synonymous variant (p.Phe21=) is not a missense change at a residue with an established pathogenic missense comparator. Details ▾Hide ▴

Evidence considered

Variant class is not missense-like
no same-residue comparator

Sources

pm5_candidates

PP2 N/APP2 applies to missense variants in a gene with a low rate of benign missense variation; this is a synonymous variant. Details ▾Hide ▴

Evidence considered

Synonymous variant
not missense

Sources

cspec ↗

PP4 VCEPThe ClinGen PTEN VCEP specifies PP4 as Not Applicable (phenotype specificity is incorporated into the PS4 rule specifications). Details ▾Hide ▴

Sources

cspec ↗

PP5 VCEPThe ClinGen PTEN VCEP specifies PP5 as Not Applicable, and the ClinVar review status is single-submitter (not a 3-star expert panel). Details ▾Hide ▴

Evidence considered

ClinVar review status 'criteria provided
single submitter'
no expert panel

Sources

cspec ↗clinvar ↗

BP1 VCEPThe ClinGen PTEN VCEP specifies BP1 as Not Applicable (PTEN disease is not primarily caused by truncating variants). Details ▾Hide ▴

Sources

cspec ↗

BP3 VCEPIn-frame indel / repeat-region criterion; not applicable to a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPThe ClinGen PTEN VCEP specifies BP6 as Not Applicable, and the ClinVar review status is single-submitter (not a 3-star expert panel). Details ▾Hide ▴

Evidence considered

ClinVar review status 'criteria provided
single submitter'
no expert panel

Sources

cspec ↗clinvar ↗

PS5 N/APS5 is not defined in the ClinGen PTEN VCEP framework and is not a standard ACMG/AMP criterion. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: PTEN
Transcript: NM_000314.8
Coding (HGVS c.): NM_000314.8:c.63C>T
Protein (HGVS p.): NP_000305.3:p.(Phe21=)
GRCh38: chr10:87864532 C>T
GRCh37: chr10:89624289 C>T
ClinVar: 927285, 488925

Gene diagram

Every interpreted variant in PTEN, mapped onto the exon structure of NM_000314.8. Select a row to find it on the plot.

PTENNM_000314.8

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in PTEN — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 1 / 1,614,140 alleles AF 6.2e-07 · 0 homozygotes

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,614,140 alleles · 0 hom

European (non-Finnish)1 / 1,179,974

8.5e-07

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19525e-07; MAF= 0.00006%, 1/1614140 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47476e-07; MAF= 0.00008%, 1/1179974 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +92 bp

0.000

SpliceAI acceptor gainat -72 bp

0.019

SpliceAI donor lossat +16 bp

0.116

SpliceAI donor gainat +105 bp

0.052

Pangolin splice lossmagnitude shown

-0.138

Pangolin splice gain

0.007

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta 0.116 (no predicted splice impact)
synonymous variant outside +7/-21 splice region

Sources

spliceai ↗cspec ↗

Evidence considered

SpliceAI max delta 0.116 (no predicted splicing impact)

Sources

spliceai ↗

Evidence considered

SpliceAI max delta 0.116 (benign range)
VarSeak not available

Still missing

VarSeak splice prediction not available for concordance

Sources

spliceai ↗cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12).

7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

Syngal S et al. · 2015

ACG clinical guideline on genetic testing and management of hereditary gastrointestinal cancer syndromes, including Cowden syndrome/PTEN. Gene-level management recommendations; NM_000314.8:c.63C>T is not discussed.
Does not name this variant
PMID 25645574 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

ACMG/AMP standards and guidelines for the interpretation of sequence variants. Provides the general classification framework; does not discuss this specific variant.
Does not name this variant
PMID 25741868 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.

Saslow D et al. · 2007

American Cancer Society guidelines for breast MRI screening as an adjunct to mammography. Cancer screening recommendations at the gene level; NM_000314.8:c.63C>T is not mentioned.
Does not name this variant
PMID 17392385 ↗
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.

American Society of Clinical Oncology expert statement on the collection and use of a cancer family history for oncology providers. No variant-level data; NM_000314.8:c.63C>T is not mentioned.
Does not name this variant
PMID 24493721 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.

ACMG Board of Directors · 2015

ACMG policy statement on updated recommendations for reporting secondary findings in clinical genome-scale sequencing. Policy-level guidance; NM_000314.8:c.63C>T is not mentioned.
Does not name this variant
PMID 25356965 ↗
Genetics of Colorectal Cancer (PDQ®): Health Professional Version.

PDQ Cancer Genetics Editorial Board · 2002

PDQ Genetics of Colorectal Cancer (Health Professional Version). Gene-level review of hereditary colorectal cancer; NM_000314.8:c.63C>T is not mentioned.
Does not name this variant
PMID 26389505 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Sherloc refinement of the ACMG-AMP variant classification criteria. Methodological framework; NM_000314.8:c.63C>T is not mentioned.
Does not name this variant
PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,614,140 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.116 Open source ↗

ClinVar 3 Likely benign · 1 Benign Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 927285)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.