PTEN c.419T>A, p.Leu140Ter

Reasoning

NM_000314.8:c.419T>A is a nonsense variant, NP_000305.3:p.(Leu140Ter) / p.(L140*), in exon 5 of the biologically relevant NM_000314.8 transcript. The PTEN VCEP decision tree assigns nonsense or frameshift variants predicted to undergo NMD with a stop codon at or 5' to p.D375 (c.1121), when the exon is present in the biologically relevant transcript, to full PVS1. c.419 is 5' to c.1121, the stop is therefore in the NMD/full-strength branch, and no named downgrade rule applies. The required variant notations were searched in PVS1_DecisionTree_PTEN.pdf.txt; no variant-specific row for this variant was present, so the governing decision-tree row was applied.

VCEP rule

Use PTEN PVS1 decision tree. ... Nonsense or frameshift | 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

• Variant assessment: NM_000314.8:c.419T>A; NP_000305.3:p.(Leu140Ter) / p.(L140*); nonsense consequence; exon 5.
• PVS1_DecisionTree_PTEN.pdf.txt, nonsense/frameshift row: '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'.
• ClinGen PTEN VCEP Version 3.2 CSPEC PVS1 entry: 'Use PTEN PVS1 decision tree.'

Still missing

• No variant-specific entry for c.419T>A, p.Leu140Ter, or p.L140* was found in PVS1_DecisionTree_PTEN.pdf.txt; the file contains the governing decision-tree row rather than variant-specific rows.

Sources

Reasoning

The PTEN VCEP permits PM2 at Supporting strength when the variant is absent in population databases or has allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; if multiple alleles are present in a subpopulation, that subpopulation frequency must be <0.00002 (0.002%). The variant is absent from the default all-comers gnomAD v2.1 and v4.1 records, corresponding to allele frequency 0 and satisfying the threshold. The VCEP does not specify a non-cancer or exome-only source for PM2, so the all-comers records are used.

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 v3.2 PM2 rule: absent in population; databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population, with a subpopulation threshold of <0.00002 (0.002%) when multiple alleles are present.
• gnomAD v2.1 all-comers: variant absent; allele frequency 0.
• gnomAD v4.1 all-comers: variant absent; allele frequency 0.

Sources

Reasoning

The variant terminates at residue 140. The PTEN VCEP defines PM1 to include residues in catalytic motifs 90-94, 123-130, and 166-168. Residue 140 lies outside all three specified regions. Although the collected Cancer Hotspots result reports a statistically significant PTEN L140 hotspot, the VCEP rule's explicit definition limits PM1 to the listed catalytic-motif residues and does not name a separate somatic-hotspot route. PM1 is therefore not met.

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

• PTEN VCEP PM1 definition: catalytic motifs at residues 90-94, 123-130, and 166-168 (NP_000305.3); the variant is at residue 140.
• Cancer Hotspots result for PTEN L140 reports a statistically significant hotspot, but the VCEP PM1 rule does not name Cancer Hotspots, COSMIC, or a separate somatic-hotspot route; its defined residue list is controlling.
• The vcep_materials.json domain_tables object is empty for PTEN, so there is no additional authoritative domain-table entry to check.

Sources

Reasoning

The PTEN VCEP specifies BA1 only when the gnomAD filtering allele frequency is >0.00056 (0.056%). The variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, so the observed allele frequency is 0 and does not exceed the BA1 threshold. The VCEP does not require a non-cancer or exome-only subset for this criterion.

VCEP rule

gnomAD Filtering allele frequency >0.00056 (0.056%)

Evidence considered

• ClinGen PTEN VCEP v3.2 BA1 rule: gnomAD Filtering allele frequency >0.00056 (0.056%).
• gnomAD v2.1 all-comers: variant absent; filtering allele frequency 0.
• gnomAD v4.1 all-comers: variant absent; filtering allele frequency 0.

Sources

Reasoning

The PTEN VCEP specifies BS1 Strong for a gnomAD filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%), and BS1 Supporting from 0.0000043 (0.00043%) up to 0.000043 (0.0043%). The variant is absent from the default all-comers gnomAD v2.1 and v4.1 records, giving an observed allele frequency of 0, below both BS1 ranges. The VCEP does not require a non-cancer or exome-only subset for this criterion.

VCEP rule

gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%) ... Allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).

Evidence considered

• ClinGen PTEN VCEP v3.2 BS1 Strong rule: gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).
• ClinGen PTEN VCEP v3.2 BS1 Supporting rule: Allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).
• gnomAD v2.1 all-comers: variant absent; filtering allele frequency 0.
• gnomAD v4.1 all-comers: variant absent; filtering allele frequency 0.

Sources

Reasoning

The variant is NP_000305.3:p.(Leu140Ter). The governing PTEN rule requires the same amino acid change as a previously established pathogenic variant, or a different variant at the same nucleotide position as a pathogenic splicing variant with an equal or greater predicted impact. The available case evidence identifies only a single-submitter ClinVar Pathogenic record for this variant and does not provide a previously established pathogenic comparator producing the same amino acid change or a pathogenic splicing comparator at c.419. Therefore PS1 cannot be evaluated from the available evidence.

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

• Variant normalization: NM_000314.8:c.419T>A produces NP_000305.3:p.(Leu140Ter).
• ClinVar record 2674368 reports Pathogenic with criteria provided by a single submitter; it does not establish a separate pathogenic comparator for PS1.
• No qualifying same-amino-acid or same-nucleotide pathogenic-splicing comparator is documented in the available case evidence.

Still missing

• A verified previously established pathogenic variant producing the same amino acid change, or a qualifying pathogenic splicing variant at the same nucleotide position with comparative in-silico evidence, is needed.

Sources

Reasoning

No proband-level de novo observation is documented in the available case evidence: there is no recorded confirmation of both maternity and paternity, no documented absence of family history, and no count of proven or assumed de novo observations. The PTEN VCEP PS2 rule therefore cannot be evaluated.

VCEP rule

De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.

Evidence considered

• The available case evidence contains no documented proband-level de novo observation, parental testing result, confirmed maternity or paternity, family-history assessment, or proven/assumed de novo observation count.
• The governing PTEN VCEP CSPEC entry for PS2 provides the required de novo observation and parental-confirmation pathways.

Still missing

• Document the affected proband's phenotype and family-history status.
• Document the variant result in the proband and parental testing results.
• Confirm maternity and paternity, or document the number of assumed and proven de novo observations.

Sources

Reasoning

The PTEN VCEP permits PS4 Very Strong for probands with specificity score ≥16, Strong for specificity score 4-15.5 or a significantly increased prevalence in affected individuals versus controls, Moderate for specificity score 2-3.5, and Supporting for a disease-specific phenotype with a single genetic etiology or specificity score 1-1.5. No PTEN-specificity score, affected/control counts, matched-ancestry population frequency comparison, or other case-control dataset is available for NM_000314.8:c.419T>A. The literature packet's candidate PS4 papers were checked through their available extracts: none reports this exact variant with affected/control prevalence data, and no paper provides a specificity score for this proband. Therefore PS4 cannot be evaluated without substituting a non-VCEP rule or inventing missing data.

VCEP rule

Probands with specificity score ≥16 (see text). OR 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. OR Probands with specificity score of 2-3.5 (see text). OR Phenotype specific for disease with single genetic etiology. Proband(s) with specificity score of 1-1.5 (see text).

Evidence considered

• ClinGen PTEN VCEP CSPEC v3.2 PS4 rules: Very Strong requires probands with specificity score ≥16; Strong requires specificity score 4-15.5 or significantly increased prevalence in affected individuals compared with controls; Moderate requires specificity score 2-3.5; Supporting requires a phenotype specific for disease with a single genetic etiology or specificity score 1-1.5.
• No case-control counts, odds ratio, 95% confidence interval, affected-patient prevalence, control prevalence, or matched-ancestry gnomAD frequency comparison for NM_000314.8:c.419T>A is present.
• PMID:24493721 discusses PTEN at the gene/disease level but the exact variant is not mentioned and no variant-specific case-control or phenotype-prevalence data are provided.
• PMID:34012068 does not mention PTEN c.419T>A or p.(L140*) and provides no variant-specific clinical or population data.
• PMID:11237521 and PMID:17218262 provide general PTEN biology or studies of other PTEN variants/models, not case-control or phenotype-specific evidence for c.419T>A.

Still missing

• A PTEN VCEP specificity score for the proband is unavailable.
• No affected-patient and unaffected/control counts or matched-ancestry population frequency comparison for this exact variant are available.

Sources

Reasoning

No proband-level presumed de novo observation is documented in the available case evidence, and there is no documented confirmation status for maternity or paternity, disease phenotype, family history, or the number of assumed and proven observations. The PTEN VCEP PM6 rule therefore cannot be evaluated.

VCEP rule

Assumed _de novo,_ but without confirmation of paternity and maternity, in proband with the disease and no family history.

Evidence considered

• The available case evidence contains no documented presumed de novo proband, parental testing result, maternity or paternity confirmation status, family-history assessment, or observation count.
• The governing PTEN VCEP CSPEC entry for PM6 defines separate very strong, strong, and moderate pathways based on proven or assumed de novo observations and parental confirmation.

Still missing

• Document the affected proband's phenotype and absence or presence of family history.
• Document whether maternity and paternity were confirmed for each presumed de novo observation.
• Document the number of presumed de novo probands and classify observations as proven or assumed.

Sources

Reasoning

No affected family members, variant-positive relatives, variant-negative relatives, pedigrees, or meiosis count are documented in the available case evidence. Consequently, co-segregation cannot be established at supporting, moderate, or strong strength under the PTEN VCEP PP1 rule.

VCEP rule

Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.

Evidence considered

• The available case evidence contains no pedigree, affected-relative testing results, family count, or informative meiosis count.
• The governing PTEN VCEP CSPEC entry for PP1 requires co-segregation in multiple affected family members and specifies strength by 3 or 4, 5 or 6, or at least 7 observed meioses across at least two families.

Still missing

• Provide pedigree and phenotype information for affected family members.
• Provide variant-testing results for relevant relatives.
• Provide the count of informative co-segregating meioses and the families represented.

Sources

Reasoning

The PTEN VCEP requires observation of the variant in the homozygous state in a healthy or PHTS-unaffected individual, with one observation if homozygous status is confirmed or two if it is not confirmed; it also specifies Supporting strength for two homozygous observations without clinical data or when BS1 is also applied. The available gnomAD records report the variant as absent and provide no homozygote observations or parental-confirmation data, so BS2 cannot be evaluated.

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. ... Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.

Evidence considered

• ClinGen PTEN VCEP v3.2 BS2 Strong 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.
• ClinGen PTEN VCEP v3.2 BS2 Supporting rule: Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.
• gnomAD v2.1 and v4.1 report the variant absent and provide no homozygote observations.

Still missing

• A qualifying homozygous observation in a healthy or PHTS-unaffected individual, with confirmation status, is unavailable.

Sources

Reasoning

No affected relatives, family pedigrees, variant testing, or non-segregation observations are documented in the available case evidence. Therefore, lack of segregation in one or more families cannot be evaluated under the PTEN VCEP BS4 rule.

VCEP rule

Lack of segregation in affected members of one family.

Evidence considered

• The available case evidence contains no affected-relative testing results, pedigree, family count, or documented lack-of-segregation observation.
• The governing PTEN VCEP CSPEC entry for BS4 assigns supporting strength for lack of segregation in one family and strong strength for lack of segregation in two or more families.

Still missing

• Provide family pedigrees and clinical status for affected members.
• Provide variant-testing results for affected relatives.
• Document whether lack of segregation occurred in one family or in two or more families.

Sources

Reasoning

The VCEP BP2 rule is applicable at Supporting strength, but the available case evidence documents no affected-proband observation showing NM_000314.8:c.419T>A in trans with a pathogenic or likely pathogenic PTEN variant and no three qualifying cis or phase-unknown observations with different pathogenic or likely pathogenic PTEN variants. The criterion therefore cannot be evaluated from the available evidence.

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 consolidated case evidence documents the index variant as NM_000314.8:c.419T>A (p.Leu140Ter) but provides no affected-proband, second-PTEN-variant, cis/trans, or phase observations needed for BP2.

Still missing

• Affected-proband observations with a second pathogenic or likely pathogenic PTEN variant, including validated phase or at least three qualifying cis/phase-unknown observations, are not documented.

Sources

Reasoning

The PTEN VCEP BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease, with the other gene/disorder highly penetrant and the patient's personal/family history demonstrating no overlap between that disorder and PTEN. The available case evidence contains no such alternate molecular diagnosis, penetrance assessment, or non-overlapping personal/family history. BP5 is therefore not assessed rather than inferred from the absence of documentation.

VCEP rule

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

• ClinGen PTEN VCEP CSPEC v3.2 BP5 rule requires an alternate molecular basis, a highly penetrant other gene/disorder, and personal/family history demonstrating no overlap between that disorder and PTEN.
• The case materials provide no qualifying alternate molecular diagnosis or the required penetrance and non-overlap clinical documentation.

Still missing

• An alternate molecular basis for disease is not documented.
• The required highly penetrant alternate disorder and non-overlapping personal/family history are not documented.

Sources