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PTENc.143A>CUncertain significance
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Variant interpretation report

PTEN c.143A>C, p.(Asn48Thr)

NM_000314.8:c.143A>C NP_000305.3:p.(Asn48Thr) 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.

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 v3.2.0. 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: 4 Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Moderate
PS3 · moderate

Mighell et al. 2018 (PMID: 29706350) massively parallel phosphatase activity assay: N48T cumulative fitness score = -3.41, which is <= the VCEP PS3_Moderate threshold of -1.11 (High_conf = True, Pass SE Filter).

PM2Supporting
PM2 · supporting

Absent from gnomAD v2.1 and v4.1, meeting the PTEN VCEP PM2_Supporting threshold of <0.00001 (<0.001%) allele frequency.

PP2Supporting
PP2 · supporting

PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PHTS (PTEN Hamartoma Tumor Syndrome), satisfying the VCEP PP2 criterion.

PP3Supporting
PP3 · supporting

REVEL score of 0.919 exceeds the PTEN VCEP PP3 threshold of >0.7 for missense variants, supporting a deleterious effect.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PS3 moderate, PM2 supporting, PP2 supporting, PP3 supporting; 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.

SpliceAI score
0.060 maximum delta

Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.

Applied · PS3 → 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 lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen PTEN VCEP v3.2.0, with the data and sources behind each one.

29 criteria with recorded statuses: 4 met · 6 not met · 9 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000314.8:c.143A>C p.(Asn48Thr) is a missense variant in PTEN exon 2.

This variant is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).

Mighell et al. 2018 PTEN saturation mutagenesis functional assay demonstrates a damaging effect with a cumulative fitness score of -3.41 (<= -1.11 threshold, High_conf = True), qualifying for PS3_Moderate per the PTEN VCEP v3.2.0.

REVEL score of 0.919 exceeds the VCEP PP3 threshold of >0.7 for missense variants.

PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PHTS (PP2).

Residue N48 lies outside the VCEP-defined catalytic motifs (90-94, 123-130, 166-168); PM1 is not met.

No de novo observations, segregation data, proband counting data, or alternate molecular basis cases were available for this variant.

ClinVar reports this variant as Uncertain significance (2 clinical laboratories, variationID 373667).

Summary of met criteria: PS3_Moderate + PM2_Supporting + PP2 + PP3. Per the PTEN VCEP final classification framework, this combination does not reach the Likely Pathogenic threshold (Rule11 requires PVS1_Strong/PS1/PS2/PS3/PS4/PM6_Strong/PP1_Strong >=1 AND PVS1_Moderate/PS3_Moderate/PS4_Moderate/PM1/PM4/PM5/PM6/PP1_Moderate ==1; Rule13 requires >=3 Moderate criteria). With 1 Moderate (PS3_Moderate) and 3 Supporting (PM2_Supporting, PP2, PP3), the variant remains classified as Uncertain significance.

Met · 4

PS3 ModerateMighell et al. 2018 (PMID: 29706350) massively parallel phosphatase activity assay: N48T cumulative fitness score = -3.41, which is <= the VCEP PS3_Moderate threshold of -1.11 (High_conf = True, Pass SE Filter). Details ▾Hide ▴
Evidence considered
  • mmc2.xlsx Table S2 row 1046: N48T Cum_score=-3.413875105
  • High_conf=True
  • Pass SE Filter
Sources
vcep_mmc2
PM2 SupportingAbsent from gnomAD v2.1 and v4.1, meeting the PTEN VCEP PM2_Supporting threshold of <0.00001 (<0.001%) allele frequency. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP2 SupportingPTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PHTS (PTEN Hamartoma Tumor Syndrome), satisfying the VCEP PP2 criterion. Details ▾Hide ▴
Evidence considered
  • PTEN VCEP v3.2.0 PP2 rule: missense in gene with low benign missense rate and missense as common disease mechanism
Sources
cspec ↗
PP3 SupportingREVEL score of 0.919 exceeds the PTEN VCEP PP3 threshold of >0.7 for missense variants, supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.919 > 0.7 threshold
Sources
revel

Not met · 6 · evaluated, threshold not reached

PM1 Residue N48 is outside the PTEN VCEP-defined catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168; NP_000305.3). Although a statistically significant hotspot was detected, the VCEP PM1 rule is restricted to residues within the specified catalytic motifs. Details ▾Hide ▴
Evidence considered
  • hotspot residue significant at N48 but outside catalytic motifs 90-94
  • 123-130
  • 166-168
Sources
cspec ↗
BA1 Variant is absent from gnomAD v2.1 and v4.1; allele frequency of 0 does not exceed the VCEP BA1 threshold of >0.00056 (>0.056%). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=0
  • gnomAD v4.1: AF=0
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Variant is absent from gnomAD; allele frequency does not fall within the VCEP BS1 range (0.0000043 to 0.00056). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=0
  • gnomAD v4.1: AF=0
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No homozygous observations of this variant in healthy or PHTS-unaffected individuals were identified; absent from gnomAD. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: hom=0
  • gnomAD v4.1: hom=0
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 Mighell et al. 2018 functional assay Cum_score = -3.41 for N48T, which does not meet the BS3_Supporting threshold of >0; the variant shows a damaging rather than benign functional effect. Details ▾Hide ▴
Evidence considered
  • mmc2.xlsx Table S2: N48T Cum_score=-3.41
  • not >0
Sources
vcep_mmc2
BP4 REVEL score of 0.919 exceeds the VCEP BP4 threshold of <0.5 for missense variants, indicating computational evidence suggests impact rather than no impact. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.919 > 0.5 BP4 threshold
Sources
revel

Not assessed · 9 · no assessment recorded

PS1 No previously established pathogenic variant with the same amino acid change (p.Asn48Thr) was identified. No other variant at c.143 with a pathogenic splicing effect was identified. Details ▾Hide ▴
Evidence considered
  • clinvar variant 373667 classified as VUS
  • no same-amino-acid P/LP entry found
Still missing
  • No established pathogenic N48T or c.143 splicing variant in ClinVar or literature
Sources
cspec ↗
PS2 No de novo observations (confirmed or assumed) were identified for this variant in the available evidence. Details ▾Hide ▴
Still missing
  • No de novo reports found in ClinVar
  • literature_pass
  • or publications
PS4 No proband counting data with PTEN specificity scores was available for this variant. ClinVar reports only 2 clinical laboratory submissions as VUS with no criterion-lead submissions usable for proband enumeration. Details ▾Hide ▴
Evidence considered
  • ClinVar variationID 373667
  • 2 submitters
  • classification Uncertain significance
Still missing
  • No proband specificity score data available
Sources
clinvar ↗
PM5 A different missense at the same residue (N48K) is reported in PMID 14675182, but its ACMG/AMP classification is not established and full-text verification was unavailable. Without a confirmed P/LP comparator at residue N48, PM5 cannot be applied. Details ▾Hide ▴
Evidence considered
  • PMID 14675182 title mentions N48K as loss-of-function but classification not established
Still missing
  • N48K classification status unknown
  • full-text unavailable for verification
Sources
14675182
PM6 No assumed de novo observations for this variant were identified in the available evidence. Details ▾Hide ▴
Still missing
  • No assumed de novo reports found
PP1 No co-segregation data was available for this variant. Details ▾Hide ▴
Still missing
  • No segregation data in ClinVar or literature_pass
BS4 No segregation data was available to evaluate lack of segregation in affected family members. Details ▾Hide ▴
Still missing
  • No segregation data available
BP2 No observations of this variant in trans with a pathogenic or likely pathogenic PTEN variant, or in cis/phase-unknown with P/LP PTEN variants, were identified. Details ▾Hide ▴
Still missing
  • No phase data available
BP5 No cases with an alternate molecular basis for disease were identified for this variant, and at least two such cases are required by the VCEP. Details ▾Hide ▴
Still missing
  • No alternate molecular basis cases identified
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant p.(Asn48Thr); the PTEN VCEP PVS1 decision tree applies only to null variants (nonsense, frameshift, canonical GT-AG splice disruptions, CNV). This variant does not fall into any PVS1-eligible bucket. Details ▾Hide ▴
Evidence considered
  • pvs1_variant_assessment bucket=other
  • pvs1_gene_context gate=eligible but variant type mismatch
Sources
cspec ↗pvs1_generic_framework ↗
PM3 VCEPPM3 applies to recessive disorders; PTEN-associated PHTS is an autosomal dominant condition. Details ▾Hide ▴
Sources
cspec ↗
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants causing protein length changes; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PP4 VCEPPTEN VCEP: phenotype specificity has been incorporated into the rule specifications for PS4 Use 2; PP4 is not applicable. Details ▾Hide ▴
Sources
cspec ↗
PP5 VCEPPP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for PTEN. Details ▾Hide ▴
Sources
cspec ↗
BP1 VCEPBP1 is not applicable to PTEN per the VCEP; missense variants are a common mechanism of disease in PTEN. Details ▾Hide ▴
Sources
cspec ↗
BP3 VCEPIn-frame deletion/insertion criterion; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for PTEN. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/ABP7 applies to synonymous or intronic variants; this is a missense variant c.143A>C p.(Asn48Thr). Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not defined in the PTEN VCEP v3.2.0 framework criteria set; replaced by PS2/PM6 hierarchy in contemporary ACMG/AMP application. Details ▾Hide ▴
Sources
cspec ↗

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.143A>C
Protein (HGVS p.)
NP_000305.3:p.(Asn48Thr)
GRCh38
chr10:87894088 A>C
GRCh37
chr10:89653845 A>C
ClinVar
373667

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…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +87 bp
0.000
SpliceAI acceptor gainat -24 bp
0.060
SpliceAI donor lossat -70 bp
0.000
SpliceAI donor gainat +21 bp
0.050
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.030

Other predictors

REVEL
0.919
BayesDel
0.224

How the predictions were used

PP3 SupportingREVEL score of 0.919 exceeds the PTEN VCEP PP3 threshold of >0.7 for missense variants, supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.919 > 0.7 threshold
Sources
revel
BP4 REVEL score of 0.919 exceeds the VCEP BP4 threshold of <0.5 for missense variants, indicating computational evidence suggests impact rather than no impact. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.919 > 0.5 BP4 threshold
Sources
revel
BP7 N/ABP7 applies to synonymous or intronic variants; this is a missense variant c.143A>C p.(Asn48Thr). Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.919. BayesDel score = 0.224372.

5 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

  • A novel loss-of-function mutation (N48K) in the PTEN gene in a Spanish patient with Cowden disease.
    No paper-specific finding is recorded.
    PMID 14675182 ↗
  • A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes.
    No paper-specific finding is recorded.
    PMID 21828076 ↗
  • Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.
    No paper-specific finding is recorded.
    PMID 25527629 ↗
  • 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.
    Richards S et al. · 2015
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • MN1 C-Terminal Truncation Syndrome.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 32790267 ↗

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.060 Open source ↗
ClinVar 2 Uncertain significance 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 373667)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.919. BayesDel score = 0.224372.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.

Somatic

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

Cancer Hotspots

This variant lies in a statistically significant hotspot.