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PTENc.431A>CUncertain significance
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Variant interpretation report

PTEN c.431A>C, p.(Lys144Thr)

NM_000314.8:c.431A>C NP_000305.3:p.(Lys144Thr) 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

NM_000314.8:c.431A>C is absent from gnomAD v2.1 and v4.1. Per PTEN VCEP specification, PM2 is applied at Supporting strength when allele frequency is below 0.001%.

PP2Supporting
PP2 · supporting

NM_000314.8:c.431A>C is a missense variant in PTEN, a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease, per VCEP PP2 specification.

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: PM2 supporting, PP2 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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV64295211, n = 3 times).

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 v3.2.0, with the data and sources behind each one.

27 criteria with recorded statuses: 2 met · 9 not met · 8 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000314.8:c.431A>C (NP_000305.3:p.Lys144Thr) is a missense variant in exon 5 of PTEN.

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

PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism (PP2_Supporting per VCEP).

Functional data from Mighell et al. 2018 saturation mutagenesis assay shows a cumulative fitness score of -0.15 for K144T, indicating mild functional impairment that does not meet PS3 or BS3 thresholds.

REVEL score of 0.691 does not exceed the VCEP PP3 threshold of >0.7; SpliceAI predicts no splice impact.

The variant lies outside the PTEN catalytic motifs (residues 90-94, 123-130, 166-168); PM1 is not met.

This variant has been reported in ClinVar as Uncertain Significance (1 submitter, VCV2687516). It has been observed somatically in 3 cancer samples (COSMIC COSV64295211).

No case-level proband data, de novo observations, co-segregation data, or same-residue pathogenic comparator variants were identified.

With 2 supporting-level pathogenic criteria (PM2_Supporting, PP2_Supporting) and no benign criteria met, the variant does not reach the combination threshold for Likely Pathogenic or Pathogenic under the PTEN VCEP v3.2.0 rules. The variant remains a Variant of Uncertain Significance.

Met · 2

PM2 SupportingNM_000314.8:c.431A>C is absent from gnomAD v2.1 and v4.1. Per PTEN VCEP specification, PM2 is applied at Supporting strength when allele frequency is below 0.001%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP2 SupportingNM_000314.8:c.431A>C is a missense variant in PTEN, a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease, per VCEP PP2 specification. Details ▾Hide ▴
Evidence considered
  • PTEN has low rate of benign missense variation
  • missense variants are a common disease mechanism
Sources
cspec ↗

Not met · 9 · evaluated, threshold not reached

PS1 No prior established pathogenic or likely pathogenic variant at amino acid residue Lys144 was identified. The only ClinVar entry at this position is VCV2687516, classified as Uncertain Significance. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV2687516 is VUS
  • PM5 candidate search returned zero comparator pathogenic variants at residue 144
Sources
clinvar ↗pm5_candidates
PS3 Functional data from Mighell et al. 2018 (PMID: 29706350) PTEN saturation mutagenesis assay yields a cumulative fitness score (Cum_score) of -0.15 for K144T (High_conf=True). This does not meet the VCEP PS3_Moderate threshold of <= -1.11, and the mild fitness reduction does not clearly satisfy PS3_Supporting criteria for a damaging effect. Details ▾Hide ▴
Evidence considered
  • Mighell et al. 2018 Table S2: K144T Cum_score = -0.1518
  • High_conf=True
  • does not reach PS3_Moderate threshold
Sources
vcep_mmc229706350
PM1 p.Lys144 is outside the PTEN catalytic motif residues defined by the VCEP (positions 90-94, 123-130, and 166-168 in NP_000305.3). Details ▾Hide ▴
Evidence considered
  • VCEP-defined catalytic motifs do not include residue 144
Sources
cspec ↗
PM5 No pathogenic or likely pathogenic missense variant at residue Lys144 was identified in ClinVar or the VCEP evidence base. The PM5 candidate search returned zero comparator variants at this residue. Details ▾Hide ▴
Evidence considered
  • Zero same-residue P/LP comparator variants identified
Sources
pm5_candidatesclinvar ↗
PP3 REVEL score of 0.691 does not exceed the VCEP PP3 threshold of >0.7 for missense variants. SpliceAI predicts no splice impact (max delta 0.00). BayesDel score of 0.059 is near neutral and does not independently support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.691 (threshold >0.7 not met)
  • SpliceAI max delta 0.00
  • BayesDel 0.059
Sources
revelbayesdelspliceai ↗
BA1 NM_000314.8:c.431A>C is absent from gnomAD. The VCEP BA1 threshold of >0.056% filtering allele frequency is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • allele frequency 0%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_000314.8:c.431A>C is absent from gnomAD. The VCEP BS1_Strong threshold of >0.0043% and BS1_Supporting threshold of >0.00043% are not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • allele frequency 0%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 Functional data from Mighell et al. 2018 (PMID: 29706350) shows a cumulative fitness score of -0.15 for K144T, which does not satisfy the VCEP BS3_Supporting threshold of a Cum_score >0. The negative score indicates mild functional impairment rather than absence of a damaging effect. Details ▾Hide ▴
Evidence considered
  • Mighell et al. 2018 Table S2: K144T Cum_score = -0.15
  • does not meet BS3_Supporting threshold of >0
Sources
vcep_mmc229706350
BP4 REVEL score of 0.691 does not meet the VCEP BP4 threshold of <0.5 for missense variants. SpliceAI predicts no splicing impact (max delta 0.00) but VCEP BP4 for splicing applies to synonymous/intronic variants, not this missense variant. Details ▾Hide ▴
Evidence considered
  • REVEL 0.691 (threshold <0.5 not met)
  • SpliceAI no splice impact but not applicable per VCEP BP4
Sources
revelspliceai ↗cspec ↗

Not assessed · 8 · no assessment recorded

PS2 No de novo observation data were identified for NM_000314.8:c.431A>C in the available evidence. Details ▾Hide ▴
Still missing
  • No de novo studies identified for this variant
PS4 No proband counts or phenotype specificity scores were available for this variant to calculate the VCEP PS4 specificity score. Details ▾Hide ▴
Still missing
  • No case-level proband data for PS4 assessment
PM6 No de novo observation data were identified for NM_000314.8:c.431A>C in the available evidence. Details ▾Hide ▴
Still missing
  • No de novo data available
PP1 No co-segregation data were available for this variant. Details ▾Hide ▴
Still missing
  • No segregation studies identified
BS2 No homozygous observations in healthy or PHTS-unaffected individuals were identified for this variant. Details ▾Hide ▴
Still missing
  • No homozygous genotype data available
BS4 No segregation data were available to assess lack of segregation in affected family members. Details ▾Hide ▴
Still missing
  • No segregation studies identified
BP2 No observations of this variant in trans or cis with other PTEN pathogenic or likely pathogenic variants were available. Details ▾Hide ▴
Still missing
  • No phase data with other PTEN variants
BP5 No evidence was identified of this variant occurring in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnoses
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000314.8:c.431A>C is a missense variant (p.Lys144Thr). The PTEN VCEP PVS1 decision tree applies exclusively to null variants (nonsense, frameshift, and canonical GT-AG splice site disruptions). Details ▾Hide ▴
Evidence considered
  • Missense variant does not trigger the PTEN PVS1 decision tree pathway
Sources
vcep_pvs1_decisiontree_pten
PP4 VCEPMarked Not Applicable by the ClinGen PTEN VCEP v3.2.0; phenotype specificity is incorporated into the PS4 rule specifications. Details ▾Hide ▴
Evidence considered
  • VCEP specification: PP4 Not Applicable
Sources
cspec ↗
PP5 VCEPMarked Not Applicable by the ClinGen PTEN VCEP v3.2.0. Details ▾Hide ▴
Evidence considered
  • VCEP specification: PP5 Not Applicable
Sources
cspec ↗
BP1 VCEPMarked Not Applicable by the ClinGen PTEN VCEP v3.2.0. Details ▾Hide ▴
Evidence considered
  • VCEP specification: BP1 Not Applicable
Sources
cspec ↗
BP3 VCEPSkipped per instructions — in-frame indel criterion not applicable to a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPMarked Not Applicable by the ClinGen PTEN VCEP v3.2.0. Details ▾Hide ▴
Evidence considered
  • VCEP specification: BP6 Not Applicable
Sources
cspec ↗
BP7 N/ANM_000314.8:c.431A>C is a missense variant. Per VCEP specification, BP7 applies only to synonymous or intronic variants at or beyond +7/-21 positions with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant does not qualify for BP7
Sources
cspec ↗
PS5 N/APP5 is marked Not Applicable by the ClinGen PTEN VCEP v3.2.0. The closely related PS5 criterion is not separately defined in the VCEP specification. Details ▾Hide ▴
Evidence considered
  • VCEP specification marks PP5 as Not Applicable
Sources
cspec ↗

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.431A>C
Protein (HGVS p.)
NP_000305.3:p.(Lys144Thr)
GRCh38
chr10:87933190 A>C
GRCh37
chr10:89692947 A>C
ClinVar
2687516
COSMIC
COSV64295211

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 -195 bp
0.000
SpliceAI acceptor gainat -69 bp
0.000
SpliceAI donor lossat +61 bp
0.000
SpliceAI donor gainat -326 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.691
BayesDel
0.059

How the predictions were used

PP3 REVEL score of 0.691 does not exceed the VCEP PP3 threshold of >0.7 for missense variants. SpliceAI predicts no splice impact (max delta 0.00). BayesDel score of 0.059 is near neutral and does not independently support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.691 (threshold >0.7 not met)
  • SpliceAI max delta 0.00
  • BayesDel 0.059
Sources
revelbayesdelspliceai ↗
BP4 REVEL score of 0.691 does not meet the VCEP BP4 threshold of <0.5 for missense variants. SpliceAI predicts no splicing impact (max delta 0.00) but VCEP BP4 for splicing applies to synonymous/intronic variants, not this missense variant. Details ▾Hide ▴
Evidence considered
  • REVEL 0.691 (threshold <0.5 not met)
  • SpliceAI no splice impact but not applicable per VCEP BP4
Sources
revelspliceai ↗cspec ↗
BP7 N/ANM_000314.8:c.431A>C is a missense variant. Per VCEP specification, BP7 applies only to synonymous or intronic variants at or beyond +7/-21 positions with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant does not qualify for BP7
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.691. BayesDel score = 0.0587913.

3 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 practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    No paper-specific finding is recorded.
    PMID 25394175 ↗
  • Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline.
    Eggener SE et al. · 2020
    No paper-specific finding is recorded.
    PMID 31829902 ↗
  • Genetic Testing and Its Clinical Application in Prostate Cancer Management: Consensus Statements from the Hong Kong Urological Association and Hong Kong Society of Uro-Oncology.
    Chiu PKF et al. · 2022
    No paper-specific finding is recorded.
    PMID 35924163 ↗

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 0.000 Open source ↗
ClinVar 1 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 (1 clinical laboratory). (ClinVarID = 2687516)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.691. BayesDel score = 0.0587913.

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 does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64295211, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.