0%
PTENc.254-1G>ALikely pathogenic
Print report
Variant interpretation report

PTEN c.254-1G>A, p.?

NM_000314.8:c.254-1G>A NP_000305.3:p.? Canonical splice · intron 4 View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PTEN

PTEN is a tumor suppressor gene that encodes a phosphatase converting the lipid messenger PIP3 back to PIP2 at the cell membrane, thereby restraining the AKT/mTOR signaling pathway that drives cell growth, proliferation, and survival. It is one of the most frequently mutated genes across many types of human cancer, and its loss promotes unchecked cell growth, survival, and genomic instability, partly through impaired DNA repair. Germline loss-of-function variants in PTEN cause Cowden syndrome, an inherited cancer predisposition disorder associated with elevated risk of breast and thyroid cancer.

NCBI Gene ↗ OncoKB ↗
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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

Met at very strong: canonical -1 acceptor disruption causes a predicted exon-5 frameshift after loss of 239 coding nucleotides and lies 5' of the PTEN c.1121 NMD threshold.

PM2Supporting
PM2 · supporting

Met at supporting strength: gnomAD v4.1 total AF is 6.220677282459805e-07, below the <0.00001 PM2 threshold, with 0 homozygotes.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Likely Pathogenic: PVS1 (very strong) plus PM2 (supporting) satisfy Rule20 of the PTEN Expert Panel framework.

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
0.993 maximum delta

Recorded SpliceAI maximum delta score: 0.993. Refer to the recorded PP3/BP4 rationale for interpretation.

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

2 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV100910231, n = 1 times).

Context only COSMIC ↗
For specialists

Technical detail

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

28 criteria with recorded statuses: 2 met · 1 not met · 14 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 is met at very strong strength under the PTEN VCEP decision tree for the canonical -1 splice-site variant producing a frameshifted exon-5 skipping consequence upstream of c.1121.

PM4 and BP3 are not applicable under the PTEN VCEP rules.

Only PS4 and BP5 are potentially applicable under the PTEN VCEP, but the available evidence lacks the required phenotype-specific, case-control, or alternate-molecular-basis data.

PP4, PP5, and BP6 are explicitly not applicable under the PTEN VCEP specification.

PM3 is explicitly not applicable under the PTEN VCEP specification. BP2 is not assessed because no qualifying pathogenic-partner observation or phase evidence is documented.

PP3 and BP4 are not_assessed because the VCEP's named SpliceAI/VarSeak concordance requirement cannot be evaluated without a VarSeak result.

BP7 is not_applicable because the canonical -1 intronic splice-site variant is outside the VCEP's +7/-21 intronic location scope.

Met · 2

PVS1 Very strongVCEPMet at very strong: canonical -1 acceptor disruption causes a predicted exon-5 frameshift after loss of 239 coding nucleotides and lies 5' of the PTEN c.1121 NMD threshold. Details ▾Hide ▴
Reasoning

NM_000314.8:c.254-1G>A is a canonical acceptor splice-site variant at -1. The case evidence identifies exon 5 as the affected exon; exon skipping removes 239 coding nucleotides (239 % 3 = 2) and shifts the reading frame. This is the GT-AG splice-site path in the PTEN VCEP decision tree, with the affected exon present in the biologically relevant NM_000314.8 transcript and the disruption far 5' of the p.D375/c.1121 NMD threshold. The VCEP tree therefore assigns full PVS1, with no named downgrade rule applicable.

VCEP rule
Use PTEN PVS1 decision tree. ... Exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD ... Stop codon or disruption at or 5’ to p.D375 (c.1121) ... Exon is present in biologically-relevant transcript NM_000314.8 ... PVS1
Evidence considered
  • pvs1_variant_assessment records NM_000314.8:c.254-1G>A as a canonical splice variant at the acceptor (-1), affecting exon 5 of 9 in the biologically relevant transcript.
  • pvs1_variant_assessment records exon 5 as c.254_492, with 239 coding nucleotides; exon skipping removes 239 nt (239 % 3 = 2) and shifts the reading frame.
  • PVS1_DecisionTree_PTEN.pdf, page 1: the GT-AG +/-1,2 splice-site branch assigns PVS1 when exon skipping or cryptic splice-site use disrupts the reading frame and is predicted to undergo NMD, the disruption is at or 5' to p.D375 (c.1121), and the exon is present in NM_000314.8.
  • The variant is c.254-1, which is 5' of the VCEP's c.1121 (p.D375) positional threshold; the case evidence identifies the exon-5 consequence as a frameshift, so no 3' non-NMD downgrade branch applies.
Still missing
  • No variant-specific row for c.254-1G>A, p.?, or p.? appears in PVS1_DecisionTree_PTEN.pdf.txt; the VCEP decision-tree branches were applied to the documented variant facts.
Sources
cspec ↗vcep_pvs1_decisiontree_pten ↗pvs1_variant_assessment
PM2 SupportingVCEPMet at supporting strength: gnomAD v4.1 total AF is 6.220677282459805e-07, below the <0.00001 PM2 threshold, with 0 homozygotes. Details ▾Hide ▴
Reasoning

The PTEN VCEP permits PM2 at supporting strength when the variant is present at less than 0.00001 allele frequency in gnomAD or another large sequenced population, with a less than 0.00002 subpopulation requirement when multiple alleles are present. gnomAD v4.1 reports total AF 6.220677282459805e-07 and highest listed subpopulation AF 8.516291665956976e-07, both below the applicable thresholds; gnomAD v2.1 and the non-cancer subsets report absence.

VCEP rule
Absent in population ... Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%).
Evidence considered
  • ClinGen PTEN VCEP Version 3.2 PM2 rule: databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; if multiple alleles are present within any subpopulation, that subpopulation allele frequency must be <0.00002 (0.002%).
  • gnomAD v4.1 reports total AF 6.220677282459805e-07 (1/1607542 alleles), highest listed subpopulation AF 8.516291665956976e-07 (1/1174220 alleles), and 0 homozygotes.
  • gnomAD v2.1 reports the variant absent; the available gnomAD v2.1 non-cancer and v3.1 non-cancer queries also report absence.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not met · 1 · evaluated, threshold not reached

BS2 VCEPNot met: gnomAD v4.1 reports 0 homozygotes, but the rule requires at least one homozygous observation in a healthy or PHTS-unaffected individual. Details ▾Hide ▴
Reasoning

The PTEN VCEP BS2 rule requires observation in the homozygous state in a healthy or PHTS-unaffected individual. gnomAD v4.1 reports 0 homozygotes for the variant, and no other qualifying homozygous observation is available; thus BS2 is not met.

VCEP rule
Observed in the homozygous state in a healthy or PHTS-unaffected individual. One observation if homozygous status confirmed, two if not confirmed. To be applied at supporting evidence level if BS1 is also applied.
Evidence considered
  • ClinGen PTEN VCEP Version 3.2 BS2 rule: observed in the homozygous state in a healthy or PHTS-unaffected individual; one observation is sufficient when homozygous status is confirmed and two when it is not confirmed.
  • gnomAD v4.1 reports 1/1607542 total alleles and 0 homozygotes; the highest listed European non-Finnish subpopulation also has 0 homozygotes.
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 14 · no assessment recorded

PS1 VCEPNot assessed: SpliceAI is 0.993, but no known pathogenic comparator at the same nucleotide position is available for the VCEP's required equal-or-greater comparison. Details ▾Hide ▴
Reasoning

The PTEN VCEP permits PS1 for a different nucleotide substitution at the same intronic splice-site position as a known pathogenic splicing variant when in silico splice-impact predictions are equal to or greater than the known variant. This case is NM_000314.8:c.254-1G>A, a canonical acceptor variant with SpliceAI maximum delta 0.993, but the available evidence does not identify a known pathogenic comparator at the same nucleotide position or provide its prediction for comparison. The amino-acid-change path is unavailable because the variant has NP_000305.3:p.? rather than a missense consequence.

VCEP rule
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, where in silico models predict impact equal to or greater than the known pathogenic variant.
Evidence considered
  • CSPEC PS1 rule: the VCEP expands PS1 to a different nucleotide substitution at the same nucleotide position as a pathogenic splicing variant, requiring in silico impact equal to or greater than the known pathogenic variant.
  • Variant assessment: NM_000314.8:c.254-1G>A is a canonical splice acceptor variant with predicted protein consequence NP_000305.3:p.?; no same-position pathogenic comparator is identified.
  • SpliceAI result: maximum delta score 0.993 for NM_000314.8:c.254-1G>A.
Still missing
  • A previously established pathogenic splicing variant at the same nucleotide position and its comparable in silico splice-impact prediction are not available.
Sources
cspec ↗spliceai ↗
PS2 Not assessed: no documented proband-level de novo observation, parental testing, or family-history status is available to evaluate the PS2 thresholds. Details ▾Hide ▴
Reasoning

The available case evidence does not document a disease-affected proband with confirmed or presumed de novo occurrence, parental maternity/paternity testing, or absence of family history. Therefore, the PTEN VCEP PS2 thresholds cannot be evaluated.

Rule
PS2
Evidence considered
  • No case-level evidence documents a confirmed or presumed de novo observation for NM_000314.8:c.254-1G>A.
  • No maternity or paternity testing, family-history status, or count of proven or assumed de novo observations is provided.
  • The PTEN VCEP CSPEC provides PS2 thresholds but the available evidence does not supply the required observations.
Still missing
  • Disease-affected proband status and phenotype are not documented for this variant.
  • Parental testing and confirmation or presumption of de novo occurrence are not documented.
  • Family-history status is not documented.
  • No additional de novo observations are documented.
Sources
cspec ↗
PS3 VCEPNot assessed: no qualifying splice assay result is available, and the VCEP's phosphatase threshold applies to missense assay data absent for this canonical splice-site variant. Details ▾Hide ▴
Reasoning

The PTEN VCEP permits PS3 for well-established functional studies showing a damaging effect, including an RNA, mini-gene, or other assay showing an impact on splicing, and separately specifies PS3_Moderate for phosphatase activity <= -1.11 per Mighell et al. 2018. This variant is a canonical splice-site variant, not a missense variant. The governing mmc2.xlsx file was searched for c.254-1G>A and p.?; no entry was found. Because no qualifying splice functional assay result is available in the reviewed evidence, PS3 cannot be assigned.

VCEP rule
Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect on the gene or gene product. * RNA, mini-gene, or other assay shows impact on splicing
Evidence considered
  • ClinGen PTEN Expert Panel CSPEC v3.2: PS3 allows well-established in vitro or in vivo functional studies supportive of a damaging effect, including an RNA, mini-gene, or other assay showing impact on splicing.
  • ClinGen PTEN Expert Panel CSPEC v3.2: PS3_Moderate uses phosphatase activity <= -1.11 per Mighell et al. 2018, PMID: 29706350.
  • Mighell et al. 2018 supplementary file mmc2.xlsx, Table S2: the table is a saturation-mutagenesis phosphatase assay table for missense variants; searches for c.254-1G>A and p.? found no matching row.
Still missing
  • No entry for c.254-1G>A or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PTEN/fulltext/mmc2.xlsx.txt.
  • A variant-specific RNA, mini-gene, or other validated splicing assay result is not available in the reviewed case evidence.
Sources
cspec ↗vcep_mmc2 ↗PMID:29706350 ↗
PS4 VCEPNot assessed: no variant-specific proband phenotype, specificity score, or case-control enrichment statistic is available for applying the PTEN VCEP PS4 rule. Details ▾Hide ▴
Reasoning

The PTEN VCEP permits PS4 from phenotype-specificity scores or, at strong level, significantly increased variant prevalence in affected individuals compared with controls. The available case evidence identifies the canonical splice variant and ClinVar classifications but provides no variant-specific proband phenotype, Cleveland Clinic score, pediatric phenotype score, independent-proband count, case-control enrichment statistic, p-value, or confidence interval. Therefore no PS4 strength can be assigned. The VCEP also states that PS4 cannot be combined with PP4, and PP4 is not applicable for this VCEP.

VCEP rule
Probands with specificity score ≥16 (see text). ... Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. ... Probands with specificity score of 2-3.5 (see text). ... Phenotype specific for disease with single genetic etiology. Proband(s) with specificity score of 1-1.5 (see text).
Evidence considered
  • The case bundle contains no variant-specific proband phenotype, Cleveland Clinic score, pediatric phenotype score, specificity score, or case-control enrichment result for NM_000314.8:c.254-1G>A.
  • ClinVar variation 377376 reports Pathogenic from two laboratories and Likely pathogenic from one laboratory, but those classifications are not phenotype-specific proband or case-control enrichment evidence and are not used to infer PS4.
Still missing
  • Variant-specific clinical phenotype or family-history data for independent probands
  • Cleveland Clinic scores or pediatric phenotype scores sufficient to calculate the specificity score
  • A sufficiently powered case-control study with variant prevalence in affected individuals and controls, including p-value and 95% confidence interval
Sources
cspec ↗PMID:17392385 ↗PMID:25190698 ↗PMID:27854360 ↗PMID:28475857 ↗
PM6 Not assessed: no presumed de novo proband observation, family-history status, or parental-confirmation details are documented for applying PM6. Details ▾Hide ▴
Reasoning

The available case evidence does not document any presumed de novo observation in a disease-affected proband, the absence of family history, or whether maternity and paternity were confirmed. The PM6 thresholds therefore cannot be evaluated.

Rule
PM6
Evidence considered
  • No presumed de novo occurrence is reported for NM_000314.8:c.254-1G>A in the available case evidence.
  • No parental confirmation status, family-history information, or count of de novo probands is provided.
  • The PTEN VCEP CSPEC provides PM6 thresholds but the available evidence does not supply the required observations.
Still missing
  • Disease-affected proband status and phenotype are not documented.
  • Presumed de novo occurrence is not documented.
  • Maternity and paternity confirmation status is not documented.
  • Family-history status is not documented.
  • The number of probands or proven and assumed observations is not documented.
Sources
cspec ↗
PP1 Not assessed: no affected relatives or informative meioses are documented, so the PP1 segregation thresholds cannot be applied. Details ▾Hide ▴
Reasoning

The available case evidence contains no affected relatives, segregation results, family count, or meiosis count. Consequently, none of the PTEN VCEP PP1 strength thresholds can be evaluated.

Rule
PP1
Evidence considered
  • No co-segregation data involving affected family members are provided for NM_000314.8:c.254-1G>A.
  • No family count or informative meiosis count is provided.
  • The PTEN VCEP CSPEC specifies PP1 thresholds of 3-4, 5-6, or at least 7 meioses, but the available evidence contains none of these data.
Still missing
  • Affected family members are not documented.
  • Variant genotypes and phenotypes of relatives are not documented.
  • Number of families is not documented.
  • Number of informative meioses is not documented.
Sources
cspec ↗
PP3 VCEPNot assessed: the rule requires concordant SpliceAI and VarSeak predictions, but only SpliceAI is available, with maximum delta 0.993. Details ▾Hide ▴
Reasoning

The PTEN VCEP PP3 rule covers synonymous or intronic variants with SpliceAI and VarSeak predictions of splicing impact, specifically SpliceAI scores 0.5-1 and VarSeak classes 4 or 5. NM_000314.8:c.254-1G>A is a canonical intronic acceptor (-1) variant. SpliceAI is available and predicts impact (DS_AL 0.993; maximum delta 0.993), but no VarSeak result or class is available. Because the required concordance of both named predictors cannot be evaluated, PP3 is not_assessed. BayesDel and other predictors are not used because they are not named for this splicing path.

VCEP rule
To be applied to synonymous or intronic variants where SpliceAl and VarSeak _in silico_ models predict a splicing impact (SpliceAl: scores 0.5-1 are consider evidence of pathogenic. VarSeak: Class 4 and 5 are consider evidence of pathogenic). ... Multiple lines of computational evidence support a deleterious effect on the gene or gene product. * Splicing variants: Concordance of SpliceAl and VarSeak * Missense variants: REVEL score > 0.7
Evidence considered
  • ClinGen PTEN VCEP PP3 instructions: for synonymous or intronic variants, SpliceAI scores 0.5-1 and VarSeak classes 4 and 5 are evidence of pathogenic splicing impact.
  • SpliceAI Lookup for NM_000314.8:c.254-1G>A: DS_AL 0.993 and maximum delta score 0.993, predicting possible splice impact.
  • No VarSeak result or class is present for this variant, so the VCEP-required SpliceAI/VarSeak concordance cannot be established.
Still missing
  • VarSeak prediction/class for NM_000314.8:c.254-1G>A is unavailable; concordance with SpliceAI cannot be evaluated.
Sources
cspec ↗spliceai ↗
BA1 VCEPNot assessed: gnomAD filtering allele frequency is unavailable, although total AF is 6.220677282459805e-07 versus the >0.00056 BA1 threshold. Details ▾Hide ▴
Reasoning

The governing PTEN rule requires the gnomAD filtering allele frequency, but the available gnomAD record reports total AF (6.220677282459805e-07; 1/1607542 alleles) and does not report a filtering AF. Therefore the specified BA1 threshold cannot be evaluated without substituting a different frequency measure.

VCEP rule
gnomAD Filtering allele frequency >0.00056 (0.056%)
Evidence considered
  • ClinGen PTEN VCEP Version 3.2 BA1 rule: gnomAD Filtering allele frequency >0.00056 (0.056%).
  • gnomAD v4.1 reports total AF 6.220677282459805e-07 from 1/1607542 alleles, with 0 homozygotes; filtering AF is not reported (grpmax_faf is null).
Still missing
  • A gnomAD filtering allele frequency for NM_000314.8:c.254-1G>A is not reported in the available evidence.
Sources
cspec ↗gnomad_v4 ↗
BS1 VCEPNot assessed: gnomAD filtering allele frequency is unavailable, while total AF is 6.220677282459805e-07 below the 0.0000043 BS1-supporting lower bound. Details ▾Hide ▴
Reasoning

The governing PTEN rule requires the gnomAD filtering allele frequency, but the available gnomAD record reports total AF (6.220677282459805e-07; highest listed subpopulation AF 8.516291665956976e-07) and does not report a filtering AF. Therefore neither the BS1 strong nor BS1 supporting interval can be evaluated without substituting a different frequency measure.

VCEP rule
gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%); supporting: Allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).
Evidence considered
  • ClinGen PTEN VCEP Version 3.2 BS1 strong rule: gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).
  • ClinGen PTEN VCEP Version 3.2 BS1 supporting rule: Allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).
  • gnomAD v4.1 reports total AF 6.220677282459805e-07 and highest listed subpopulation AF 8.516291665956976e-07; filtering AF is not reported (grpmax_faf is null).
Still missing
  • A gnomAD filtering allele frequency for NM_000314.8:c.254-1G>A is not reported in the available evidence.
Sources
cspec ↗gnomad_v4 ↗
BS3 VCEPNot assessed: no benign splicing assay demonstrates no impact, and the VCEP's phosphatase criterion applies to missense assay data absent for this canonical splice-site variant. Details ▾Hide ▴
Reasoning

The PTEN VCEP requires well-established in vitro or in vivo functional studies showing no damaging effect for BS3 Strong and permits BS3 Supporting for an in vitro or in vivo study showing no damaging effect, including phosphatase activity >0 per Mighell et al. 2018. For intronic variants, the VCEP specifically requires RNA, mini-gene, or another splicing assay demonstrating no splicing impact. This variant is a canonical splice-site variant, and no variant-specific benign splicing assay result is available. The governing mmc2.xlsx file was searched for c.254-1G>A and p.?; no entry was found, so BS3 cannot be assigned.

VCEP rule
Well-established _in vitro_ or _in vivo_ functional studies shows no damaging effect on protein function. To be applied to intronic or synonymous variants, RNA, mini-gene or other splicing assay demonstrating no splicing impact.
Evidence considered
  • ClinGen PTEN Expert Panel CSPEC v3.2: BS3 Strong requires well-established in vitro or in vivo functional studies showing no damaging effect and, for intronic or synonymous variants, an RNA, mini-gene, or other splicing assay demonstrating no splicing impact.
  • ClinGen PTEN Expert Panel CSPEC v3.2: BS3 Supporting includes phosphatase activity >0 per Mighell et al. 2018, PMID: 29706350.
  • Mighell et al. 2018 supplementary file mmc2.xlsx, Table S2: the table is a saturation-mutagenesis phosphatase assay table for missense variants; searches for c.254-1G>A and p.? found no matching row.
Still missing
  • No entry for c.254-1G>A or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PTEN/fulltext/mmc2.xlsx.txt.
  • A variant-specific RNA, mini-gene, or other validated assay demonstrating no splicing impact is not available in the reviewed case evidence.
Sources
cspec ↗vcep_mmc2 ↗PMID:29706350 ↗
BS4 Not assessed: no affected-family non-segregation observation is documented for evaluating BS4 at supporting or strong strength. Details ▾Hide ▴
Reasoning

The available case evidence contains no affected family members with documented non-segregation or other informative segregation results. The PTEN VCEP BS4 thresholds for one or at least two families therefore cannot be evaluated.

Rule
BS4
Evidence considered
  • No lack-of-segregation observation in affected members of one or more families is provided for NM_000314.8:c.254-1G>A.
  • No informative affected-relative genotypes or phenotypes are provided.
  • The PTEN VCEP CSPEC defines BS4 for lack of segregation in affected members of one family or two or more families, but the available evidence contains no such observation.
Still missing
  • Affected family members are not documented.
  • Relative genotypes and phenotypes are not documented.
  • No non-segregation observation is documented.
  • Number of affected families is not documented.
Sources
cspec ↗
BP2 VCEPNot assessed: no documented pathogenic PTEN variant in cis or trans, or phase result, establishes either VCEP BP2 pathway. Details ▾Hide ▴
Reasoning

BP2 cannot be assessed from the available evidence. The case documents no pathogenic or likely pathogenic PTEN variant in trans, no three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants, and no phase or affected-proband allelic observation establishing either VCEP BP2 pathway.

VCEP rule
Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.
Evidence considered
  • The case evidence contains no documented pathogenic or likely pathogenic PTEN variant in trans with NM_000314.8:c.254-1G>A.
  • The case evidence contains no three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants, and no molecular or familial phase result.
  • The available literature extracts do not report variant-specific phase, cis/trans, affected-proband, or pathogenic-partner observations for NM_000314.8:c.254-1G>A.
Still missing
  • Documented pathogenic or likely pathogenic PTEN variant observed in trans
  • At least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants
  • Molecular or familial phasing documentation and affected-proband context
Sources
cspec ↗
BP4 VCEPNot assessed: the rule requires concordant benign SpliceAI and VarSeak predictions, but SpliceAI's maximum delta is 0.993 and VarSeak is unavailable. Details ▾Hide ▴
Reasoning

The PTEN VCEP BP4 rule covers synonymous or intronic variants with SpliceAI and VarSeak predictions of no splicing impact, specifically SpliceAI scores 0-0.2 and VarSeak classes 1 or 2. NM_000314.8:c.254-1G>A is a canonical intronic acceptor (-1) variant. SpliceAI is available and predicts impact (DS_AL 0.993; maximum delta 0.993), not no impact, while no VarSeak result or class is available. Because the required concordance of both named predictors cannot be evaluated, BP4 is not_assessed. BayesDel and other predictors are not used because they are not named for this splicing path.

VCEP rule
To be applied to synonymous or intronic variants where SpliceAl and VarSeak _in silico_ models predict no splicing impact (SpliceAl: scores 0-0.2 are considered evidence of benign. VarSeak: Class 1 and 2 are considered evidence of benign). ... Multiple lines of computational evidence suggest no impact on gene or gene product.  * Splicing variants: Concordance of SpliceAl and VarSeak * Missense variants: REVEL scores \< 0.5
Evidence considered
  • ClinGen PTEN VCEP BP4 instructions: for synonymous or intronic variants, SpliceAI scores 0-0.2 and VarSeak classes 1 and 2 are evidence of benign splicing impact.
  • SpliceAI Lookup for NM_000314.8:c.254-1G>A: DS_AL 0.993 and maximum delta score 0.993, predicting possible splice impact rather than no impact.
  • No VarSeak result or class is present for this variant, so the VCEP-required SpliceAI/VarSeak concordance cannot be established.
Still missing
  • VarSeak prediction/class for NM_000314.8:c.254-1G>A is unavailable; the VCEP-required benign concordance cannot be evaluated.
Sources
cspec ↗spliceai ↗
BP5 VCEPNot assessed: no two cases with an alternate highly penetrant molecular diagnosis and documented non-overlapping PTEN history meet the BP5 requirements. Details ▾Hide ▴
Reasoning

The PTEN VCEP requires a variant to be found in a case with an alternate molecular basis for disease, requires at least two such cases, requires the other gene/disorder to be highly penetrant, and requires the patient's personal or family history to show no overlap between that disorder and PTEN. The available evidence documents no alternate molecular diagnosis, no two qualifying cases, and no personal or family-history non-overlap analysis. Therefore BP5 is not assessed.

VCEP rule
At least two such cases are required for criteria to apply. In addition, the other gene/disorder must be considered highly penetrant AND the patient’s personal/family history must demonstrate no overlap between the other gene and PTEN. ... Variant found in a case with an alternate molecular basis for disease. Other gene/disorder must be considered highly penetrant AND patient’s personal/family history must demonstrate no overlap between other gene and PTEN.
Evidence considered
  • No case-level evidence in the reviewed materials identifies an alternate molecular diagnosis for the patient or documents two qualifying cases.
  • No personal or family-history evidence demonstrates the VCEP-required absence of overlap between an alternate disorder and PTEN.
Still missing
  • At least two independent cases with an alternate molecular basis for disease
  • Evidence that each alternate gene/disorder is highly penetrant
  • Personal and family-history data demonstrating no phenotype overlap between the alternate disorder and PTEN
Sources
cspec ↗
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PM1 N/ANot applicable: The variant has no encoded amino-acid residue, while the VCEP PM1 domains are limited to residues 90-94, 123-130, and 166-168. Details ▾Hide ▴
Reasoning

The VCEP defines PM1 for a variant located in a mutational hotspot and/or critical functional domain, specifically PTEN catalytic-motif residues 90-94, 123-130, and 166-168. This variant is the canonical intronic splice-site change NM_000314.8:c.254-1G>A with no encoded amino-acid residue (NP_000305.3:p.?), so it does not lie at one of the residue locations named by the governing PM1 rule. vcep_materials.json has no PTEN domain_tables entry; the complete applicable VCEP residue list is therefore the CSPEC list itself.

VCEP rule
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 (NP_ 000305.3)
Evidence considered
  • CSPEC PM1 specification: PTEN catalytic motifs are the WPD loop residues 90-94, P-loop residues 123-130, and TI-loop residues 166-168 (NP_000305.3).
  • Variant assessment: NM_000314.8:c.254-1G>A is a canonical intronic acceptor variant with NP_000305.3:p.? and therefore has no encoded residue to compare with the listed domains.
  • vcep_materials.json domain_tables is empty for PTEN; no additional authoritative domain-table entries were available.
Sources
cspec ↗
PM3 VCEPNot applicable: the PTEN VCEP explicitly marks PM3 as "Not Applicable." Details ▾Hide ▴
Reasoning

PM3 is not applicable under the ClinGen PTEN Expert Panel Specifications, Version 3.2, which explicitly marks PM3 as not applicable. No recessive allelic evidence is needed for this disposition.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen PTEN Expert Panel Specifications, Version 3.2 CSPEC criteria entry for PM3: applicability is "Not Applicable."
Sources
cspec ↗
PM4 N/ANot applicable: the variant is a canonical splice-site substitution with a predicted frameshift, whereas PTEN PM4 covers in-frame length changes, stop-loss, catalytic-motif changes, or protein extension. Details ▾Hide ▴
Reasoning

The PTEN VCEP PM4 rule is limited to protein length changes from in-frame insertions or deletions in a non-repeat region, stop-loss variants, in-frame changes affecting a catalytic motif, or protein extensions. This variant is a canonical splice-site substitution with a predicted frameshift consequence, not an in-frame insertion/deletion, stop-loss, catalytic-motif in-frame change, or protein extension.

VCEP rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif (see PM1), and variants causing protein extension.
Evidence considered
  • The PTEN CSPEC PM4 entry states: protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants; it also includes in-frame catalytic-motif changes and protein extension.
  • pvs1_variant_assessment classifies NM_000314.8:c.254-1G>A as a canonical splice variant and documents a frameshift if exon 5 is skipped.
Sources
cspec ↗pvs1_variant_assessment
PM5 N/ANot applicable: PM5 requires a missense change at an amino-acid residue, but this variant is a canonical splice-site change with protein consequence p.?. Details ▾Hide ▴
Reasoning

The VCEP PM5 rule requires a missense change at an amino-acid residue with a different pathogenic or likely pathogenic missense change and a BLOSUM62 comparison. NM_000314.8:c.254-1G>A is a canonical splice-site variant with NP_000305.3:p.?, not a missense change, so PM5 does not apply.

VCEP rule
Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant.
Evidence considered
  • CSPEC PM5 rule requires a missense change at an amino-acid residue and a different pathogenic or likely pathogenic missense comparator with BLOSUM62 score comparison.
  • Variant assessment: NM_000314.8:c.254-1G>A is classified as canonical_splice and has NP_000305.3:p.? rather than a missense protein change.
Sources
cspec ↗
PP2 N/ANot applicable: PP2 requires a missense variant, whereas this variant is a canonical splice-site change with protein consequence p.?. Details ▾Hide ▴
Reasoning

The VCEP PP2 rule is restricted to a missense variant in a gene with a low rate of benign missense variation and missense as a common disease mechanism. NM_000314.8:c.254-1G>A is a canonical splice-site variant with NP_000305.3:p.?, not a missense variant, so PP2 is not applicable.

VCEP rule
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Evidence considered
  • CSPEC PP2 rule applies to a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
  • Variant assessment: NM_000314.8:c.254-1G>A is classified as canonical_splice and has NP_000305.3:p.?.
Sources
cspec ↗
PP4 VCEPNot applicable: the PTEN VCEP explicitly designates PP4 as not applicable and incorporates phenotype specificity into PS4 Use 2. Details ▾Hide ▴
Reasoning

The PTEN VCEP marks PP4 as Not Applicable and states that phenotype specificity has been incorporated into PS4 Use 2. PP4 is therefore not evaluated independently, regardless of the clinical phenotype information available.

VCEP rule
Not applicable
Evidence considered
  • The PTEN VCEP CSPEC entry lists PP4 applicability as Not applicable and directs phenotype-specific evidence to PS4 Use 2.
Sources
cspec ↗
PP5 VCEPNot applicable: the PTEN VCEP prohibits use of PP5, so ClinVar or published pathogenic classifications cannot support this criterion. Details ▾Hide ▴
Reasoning

The PTEN VCEP marks PP5 as Not Applicable for this VCEP and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ClinVar classifications and published statements therefore cannot be converted into PP5 under this governing framework.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The PTEN VCEP CSPEC entry marks PP5 Not Applicable for this VCEP; this determination does not depend on the available ClinVar submissions or publications.
Sources
cspec ↗
BP1 VCEPNot applicable: The PTEN VCEP explicitly states that BP1 is not applicable to PTEN. Details ▾Hide ▴
Reasoning

The PTEN VCEP explicitly marks BP1 as not applicable to PTEN. This canonical splice-site variant therefore cannot receive BP1 under the governing framework.

VCEP rule
This rule is not applicable to PTEN.
Evidence considered
  • CSPEC BP1 applicability: the PTEN VCEP states, "This rule is not applicable to PTEN."
Sources
cspec ↗
BP3 VCEPNot applicable: the PTEN VCEP explicitly states that BP3 is not applicable to PTEN, regardless of the variant's repeat-region context. Details ▾Hide ▴
Reasoning

The PTEN VCEP explicitly marks BP3 as not applicable to PTEN, so repeat-region context cannot activate this criterion for this gene.

VCEP rule
This rule is not applicable to PTEN.
Evidence considered
  • The PTEN CSPEC BP3 entry states: This rule is not applicable to PTEN.
Sources
cspec ↗
BP6 VCEPNot applicable: the PTEN VCEP prohibits use of BP6, regardless of any reputable-source benign report. Details ▾Hide ▴
Reasoning

The PTEN VCEP marks BP6 as Not Applicable for this VCEP and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. No benign report can be converted into BP6 under this framework.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The PTEN VCEP CSPEC entry marks BP6 Not Applicable for this VCEP; no benign-source evidence is used.
Sources
cspec ↗
BP7 N/ANot applicable: c.254-1G>A is an intronic -1 splice-site variant, outside BP7's scope of intronic variants at or beyond -21. Details ▾Hide ▴
Reasoning

The PTEN VCEP BP7 rule applies to synonymous or intronic variants at or beyond +7/-21. NM_000314.8:c.254-1G>A is an intronic canonical acceptor (-1) variant, which lies within the -1/-21 canonical splice-site interval and is therefore outside BP7's stated intronic scope. BP7 is not_applicable before evaluating splicing predictions.

VCEP rule
Intronic variants must be positioned at or beyond +7/-21. ... A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.
Evidence considered
  • ClinGen PTEN VCEP BP7 instruction: intronic variants must be positioned at or beyond +7/-21.
  • Case variant is NM_000314.8:c.254-1G>A, an intronic canonical acceptor (-1) variant; therefore it is outside BP7's stated location scope.
Sources
cspec ↗

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.254-1G>A
Protein (HGVS p.)
NP_000305.3:p.?
GRCh38
chr10:87933012 G>A
GRCh37
chr10:89692769 G>A
Location and type
Intron 4 · canonical splice
ClinVar
377376
COSMIC
COSV100910231

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 1 / 1,607,542 alleles AF 6.22e-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 / 1,607,542 alleles · 0 hom
European (non-Finnish)1 / 1,174,220 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= 6.22068e-07; MAF= 0.00006%, 1/1607542 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.51629e-07; MAF= 0.00009%, 1/1174220 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 +1 bp
0.993
SpliceAI acceptor gainat -17 bp
0.379
SpliceAI donor lossat +239 bp
0.006
SpliceAI donor gainat +7 bp
0.000
Pangolin splice lossmagnitude shown
-0.864
Pangolin splice gain
0.550

Other predictors

REVEL
Not available
BayesDel
0.319

How the predictions were used

PP3 VCEPNot assessed: the rule requires concordant SpliceAI and VarSeak predictions, but only SpliceAI is available, with maximum delta 0.993. Details ▾Hide ▴
Reasoning

The PTEN VCEP PP3 rule covers synonymous or intronic variants with SpliceAI and VarSeak predictions of splicing impact, specifically SpliceAI scores 0.5-1 and VarSeak classes 4 or 5. NM_000314.8:c.254-1G>A is a canonical intronic acceptor (-1) variant. SpliceAI is available and predicts impact (DS_AL 0.993; maximum delta 0.993), but no VarSeak result or class is available. Because the required concordance of both named predictors cannot be evaluated, PP3 is not_assessed. BayesDel and other predictors are not used because they are not named for this splicing path.

VCEP rule
To be applied to synonymous or intronic variants where SpliceAl and VarSeak _in silico_ models predict a splicing impact (SpliceAl: scores 0.5-1 are consider evidence of pathogenic. VarSeak: Class 4 and 5 are consider evidence of pathogenic). ... Multiple lines of computational evidence support a deleterious effect on the gene or gene product. * Splicing variants: Concordance of SpliceAl and VarSeak * Missense variants: REVEL score > 0.7
Evidence considered
  • ClinGen PTEN VCEP PP3 instructions: for synonymous or intronic variants, SpliceAI scores 0.5-1 and VarSeak classes 4 and 5 are evidence of pathogenic splicing impact.
  • SpliceAI Lookup for NM_000314.8:c.254-1G>A: DS_AL 0.993 and maximum delta score 0.993, predicting possible splice impact.
  • No VarSeak result or class is present for this variant, so the VCEP-required SpliceAI/VarSeak concordance cannot be established.
Still missing
  • VarSeak prediction/class for NM_000314.8:c.254-1G>A is unavailable; concordance with SpliceAI cannot be evaluated.
Sources
cspec ↗spliceai ↗
BP4 VCEPNot assessed: the rule requires concordant benign SpliceAI and VarSeak predictions, but SpliceAI's maximum delta is 0.993 and VarSeak is unavailable. Details ▾Hide ▴
Reasoning

The PTEN VCEP BP4 rule covers synonymous or intronic variants with SpliceAI and VarSeak predictions of no splicing impact, specifically SpliceAI scores 0-0.2 and VarSeak classes 1 or 2. NM_000314.8:c.254-1G>A is a canonical intronic acceptor (-1) variant. SpliceAI is available and predicts impact (DS_AL 0.993; maximum delta 0.993), not no impact, while no VarSeak result or class is available. Because the required concordance of both named predictors cannot be evaluated, BP4 is not_assessed. BayesDel and other predictors are not used because they are not named for this splicing path.

VCEP rule
To be applied to synonymous or intronic variants where SpliceAl and VarSeak _in silico_ models predict no splicing impact (SpliceAl: scores 0-0.2 are considered evidence of benign. VarSeak: Class 1 and 2 are considered evidence of benign). ... Multiple lines of computational evidence suggest no impact on gene or gene product.  * Splicing variants: Concordance of SpliceAl and VarSeak * Missense variants: REVEL scores \< 0.5
Evidence considered
  • ClinGen PTEN VCEP BP4 instructions: for synonymous or intronic variants, SpliceAI scores 0-0.2 and VarSeak classes 1 and 2 are evidence of benign splicing impact.
  • SpliceAI Lookup for NM_000314.8:c.254-1G>A: DS_AL 0.993 and maximum delta score 0.993, predicting possible splice impact rather than no impact.
  • No VarSeak result or class is present for this variant, so the VCEP-required SpliceAI/VarSeak concordance cannot be established.
Still missing
  • VarSeak prediction/class for NM_000314.8:c.254-1G>A is unavailable; the VCEP-required benign concordance cannot be evaluated.
Sources
cspec ↗spliceai ↗
BP7 N/ANot applicable: c.254-1G>A is an intronic -1 splice-site variant, outside BP7's scope of intronic variants at or beyond -21. Details ▾Hide ▴
Reasoning

The PTEN VCEP BP7 rule applies to synonymous or intronic variants at or beyond +7/-21. NM_000314.8:c.254-1G>A is an intronic canonical acceptor (-1) variant, which lies within the -1/-21 canonical splice-site interval and is therefore outside BP7's stated intronic scope. BP7 is not_applicable before evaluating splicing predictions.

VCEP rule
Intronic variants must be positioned at or beyond +7/-21. ... A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.
Evidence considered
  • ClinGen PTEN VCEP BP7 instruction: intronic variants must be positioned at or beyond +7/-21.
  • Case variant is NM_000314.8:c.254-1G>A, an intronic canonical acceptor (-1) variant; therefore it is outside BP7's stated location scope.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.31948.

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

  • 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.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability.
    Tatton-Brown K et al. · 2017
    The paper does not report the specific PTEN c.254-1G>A variant. It reports pathogenic PTEN mutations in 16 individuals with overgrowth and intellectual disability, but provides no individual-level variant data or evidence that this variant contributes to a phenotype-specific or case-control analysis.
    Does not name this variant
    PMID 28475857 ↗
    Quoted passage
    By far the most common cause was a mutation in NSD1 (240 cases, 34%), followed by EZH2 (34, 4.8%), DNMT3A (18, 2.5%), PTEN (MIM: 601728) (16, 2.3%), NFIX (MIM: 164005) (14, 2.0%), CHD8 (MIM: 610528) (12, 1.7%), BRWD3 (MIM: 300553) (7, 1.0%), HIST1H1E (5, 0.7%), PPP2R5D (3, 0.4%), (2 cases each) EED (MIM: 605984), GPC3 (MIM: 300037), and MTOR (MIM: 601231), and (1 case each) AKT3 (MIM: 611223) and PIK3CA (MIM: 171834) (Table S1).

    Results, Contribution of Gene Mutations to OGID; Functional Network Analyses

  • American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
    Saslow D et al. · 2007
    This paper does not report the specific PTEN variant c.254-1G>A or any variant-level functional, clinical, segregation, or population data. It states only that inherited mutations in PTEN are associated with increased breast cancer risk in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome; the paper notes that these conditions are very rare and that accurate prevalence figures are unavailable.
    Does not name this variant
    PMID 17392385 ↗
    Quoted passage
    A high risk of breast cancer also occurs with mutations in the TP53 gene (Li-Fraumeni syndrome) and the PTEN gene (Cowden and Bannayan-Riley-Ruvalcaba syndromes). Accurate prevalence figures are not available, but these conditions appear to be very rare.

    Genetic Testing section, page 77

  • Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.
    Schaefer GB et al. · 2013
    No paper-specific finding is recorded.
    PMID 23519317 ↗
  • ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
    Green RC et al. · 2013
    No paper-specific finding is recorded.
    PMID 23788249 ↗
  • Genetic/familial high-risk assessment: breast and ovarian, version 1.2014.
    Daly MB et al. · 2014
    The paper does not mention PTEN c.254-1G>A or a corresponding protein change. It describes the PTEN hamartoma tumor syndrome spectrum and reports high estimated PTEN mutation penetrance, but provides no variant-specific functional, segregation, case, or population-frequency data for this variant.
    Does not name this variant
    PMID 25190698 ↗
    Quoted passage
    The spectrum of disorders resulting from germline mutations in PTEN9 are referred to as PHTS. The spectrum of PHTS includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Adult Lhermitte-Duclos disease, Proteus-like syndrome,10–12 and autism spectrum disorders with macrocephaly.11–13 The estimated penetrance of PTEN mutation is high (≈80%).14

    Discussion, PTEN Hamartoma Tumor Syndrome, page 1332

  • Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
    Kalia SS et al. · 2017
    The paper lists PTEN as the gene associated with PTEN hamartoma tumor syndrome in the ACMG SF v2.0 minimum list for secondary findings. It does not provide variant-specific observations, functional data, segregation data, or population-frequency data for c.254-1G>A.
    Does not name this variant
    PMID 27854360 ↗
    Quoted passage
    PTEN hamartoma tumor syndrome

    Table 1, ACMG SF v2.0 genes and associated phenotypes recommended for return of secondary findings in clinical sequencing

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

gnomAD v4.1 1 / 1,607,542 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.993 Open source ↗
ClinVar 2 Pathogenic · 1 Likely pathogenic Open source ↗
COSMIC Captured COSMIC 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

This variant is present in gnomAD v4.1 (AF= 6.22068e-07; MAF= 0.00006%, 1/1607542 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.51629e-07; MAF= 0.00009%, 1/1174220 alleles, homozygotes = 0).

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 Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 377376)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.31948.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV100910231, n = 1 times).