PTEN c.69_73del, p.Leu23PhefsTer19

Reasoning

NM_000314.8:c.69_73del is a frameshift, p.(Leu23PhefsTer19), in exon 1. The PTEN decision tree assigns full PVS1 when a nonsense or frameshift variant is predicted to undergo NMD because the stop codon or disruption is at or 5' to p.D375 (c.1121) and the exon is present in biologically-relevant transcript NM_000314.8. This variant is far 5' of c.1121 and exon 1 is present in NM_000314.8, so the full, non-downgraded tier applies.

VCEP rule

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

• PVS1_DecisionTree_PTEN.pdf.txt, page 1, nonsense or frameshift row: a variant predicted to undergo NMD with a stop codon or disruption at or 5' to p.D375 (c.1121), in an exon present in biologically-relevant transcript NM_000314.8, is assigned PVS1.
• pvs1_variant_assessment: NM_000314.8:c.69_73del; NP_000305.3:p.(Leu23PhefsTer19), p.(L23Ffs*19); exon 1; consequence class frameshift.
• The variant's c.69 position is 5' to the VCEP threshold c.1121, and exon 1 is present in the governing transcript NM_000314.8.

Still missing

• No exact variant entry was found in PVS1_DecisionTree_PTEN.pdf.txt for c.69_73del, p.Leu23PhefsTer19, or p.L23Ffs*19; the governing decision-tree path was applied.

Sources

Reasoning

The ClinGen PTEN Expert Panel Version 3.2 specification permits PM2 at Supporting strength when the variant is absent or present at an allele frequency below 0.00001 (0.001%) in gnomAD or another large sequenced population; if multiple alleles occur in a subpopulation, that subpopulation frequency must be below 0.00002 (0.002%). The variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, satisfying the absence requirement.

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

• The PTEN VCEP Version 3.2 PM2 rule requires absence or allele frequency <0.00001 (0.001%) in gnomAD; any subpopulation with multiple alleles must remain <0.00002 (0.002%).
• The default all-comers gnomAD v2.1 record reports the variant absent.
• The default all-comers gnomAD v4.1 record reports the variant absent.

Sources

Reasoning

The variant affects residue 23. The PTEN VCEP defines PM1's critical functional regions as WPD loop residues 90-94, P-loop residues 123-130, and TI-loop residues 166-168; residue 23 is outside all three. Although the case evidence reports a Cancer Hotspots L23 hotspot, the PTEN VCEP's PM1 specification does not name Cancer Hotspots, COSMIC, or another somatic-hotspot route, so that observation cannot establish PM1 under this VCEP-only interpretation.

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

• The PTEN VCEP defines the complete approved PM1 regions as WPD loop 90-94, P-loop/phosphatase core 123-130, and TI-loop 166-168 (NP_000305.3); the variant is p.(Leu23PhefsTer19), residue 23.
• Cancer Hotspots evidence reports a statistically significant PTEN L23 hotspot, but the VCEP PM1 specification does not name Cancer Hotspots, COSMIC, or a somatic-hotspot route; therefore the hotspot observation is not an allowed PM1 route here.

Sources

Reasoning

The ClinGen PTEN Expert Panel Version 3.2 specification requires BA1 for a gnomAD filtering allele frequency greater than 0.00056 (0.056%). The variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, so no allele frequency meets or exceeds this stand-alone benign threshold.

VCEP rule

gnomAD Filtering allele frequency >0.00056 (0.056%)

Evidence considered

• The PTEN VCEP Version 3.2 BA1 rule is gnomAD Filtering allele frequency >0.00056 (0.056%).
• The default all-comers gnomAD v2.1 record reports the variant absent.
• The default all-comers gnomAD v4.1 record reports the variant absent.

Sources

Reasoning

The ClinGen PTEN Expert Panel Version 3.2 specification assigns 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 gnomAD v4.1 records, providing no frequency in either interval.

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

• The PTEN VCEP Version 3.2 BS1 Strong rule is gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).
• The PTEN VCEP Version 3.2 BS1 Supporting rule is allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).
• The default all-comers gnomAD v2.1 record reports the variant absent.
• The default all-comers gnomAD v4.1 record reports the variant absent.

Sources

Reasoning

The ClinGen PTEN Expert Panel Version 3.2 specification requires the variant to be observed in the homozygous state in a healthy or PHTS-unaffected individual; one observation is sufficient when homozygosity is confirmed, and two are required when it is unconfirmed. The variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, so no homozygous observation is available.

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

• The PTEN VCEP Version 3.2 BS2 Strong rule requires observation in the homozygous state in a healthy or PHTS-unaffected individual; one observation is sufficient if homozygous status is confirmed, and two if not confirmed.
• The default all-comers gnomAD v2.1 record reports the variant absent.
• The default all-comers gnomAD v4.1 record reports the variant absent.

Sources

Reasoning

No documented de novo observation is available for this variant: the available evidence contains no proband-level parental testing, confirmation of both maternity and paternity, or family-history assessment. The criterion therefore cannot be evaluated against the PTEN VCEP requirement.

VCEP rule

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

Evidence considered

• No proband-level parental testing, maternity/paternity confirmation, family-history assessment, or independent de novo observation is documented in the available case evidence.

Still missing

• Affected proband phenotype and disease diagnosis
• Parental testing confirming both maternity and paternity
• Family-history assessment
• Any additional independent de novo observations

Sources

Reasoning

The PTEN VCEP permits PS4 from a sufficiently powered case-control study showing an odds ratio >2 for a PHTS component phenotype with p<0.05 and a 95% confidence-interval lower limit >1.5, or from summed phenotype-specificity scores across independent probands. The available case evidence contains no affected/control counts, allele frequencies for a matched control comparison, odds ratio, confidence interval, p-value, Cleveland Clinic scores, pediatric phenotype scores, or variant-specific proband phenotype observations. The literature_pass.json packet has an empty packet.ai_classified_papers list, so there are no pre-classified PS4 papers to verify. PS4 is therefore not assessed; the available population absence does not substitute for the VCEP's case-control or specificity evidence, and no PS4 decision is made in combination with PP4.

VCEP rule

This criterion may not be applied if BS1 applies.  Phenotype specificity scores are added across independent probands and calculated as follows: Adults:  * 1 point per proband with Cleveland Clinic (CC) score ≥ 30 (Tan 2011) * 0.5 points per proband with CC score of 25-29. Children: * 1 point per proband with pediatric phenotype score ≥ 5 (please see supplementary information in manuscript for scoring rubric). * 0.5 points per proband with pediatric phenotype score of 4, but autism/developmental delay/intellectual disability may not contribute to the score. PS4\_Very Strong: Probands with specificity score ≥16 (see text). PS4: Probands with specificity score of 4-15.5. PS4\_Moderate: Probands with specificity score of 2-3.5. PS4\_Supporting: Proband(s) with specificity score of 1-1.5 (see text).

Evidence considered

• ClinGen PTEN VCEP v3.2 PS4 instructions: sufficiently powered case-control evidence requires odds ratio >2 for a PHTS component phenotype, p<0.05, and a 95% confidence-interval lower limit >1.5; the alternative is a summed phenotype-specificity score across independent probands.
• The case evidence has no affected/control counts, matched control frequency, odds ratio, confidence interval, p-value, Cleveland Clinic score, pediatric phenotype score, or variant-specific proband phenotype observations.
• literature_pass.json packet.ai_classified_papers is empty; consequently, no paper was pre-classified as PS4 and no variant-specific PS4 paper could be verified from that packet.

Still missing

• Affected and control carrier counts or matched-ancestry control frequency for NM_000314.8:c.69_73del
• Case-control p-value and 95% confidence interval, if a case-control study exists
• Variant-specific independent-proband Cleveland Clinic scores or pediatric phenotype scores

Sources

Reasoning

No assumed or presumed de novo observation is documented for this variant. The available evidence does not establish an affected proband, absence of family history, or whether maternity and paternity were unconfirmed, so none of the VCEP PM6 strength thresholds can 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

• No assumed or presumed de novo observation, affected proband record, parental-confirmation status, or family-history assessment is documented in the available case evidence.

Still missing

• Affected proband phenotype and disease diagnosis
• Evidence that the variant is de novo or presumed de novo
• Maternity and paternity confirmation status
• Family-history assessment
• Additional qualifying de novo observations

Sources

Reasoning

No affected relatives, genotype-phenotype observations, family pedigrees, or meioses are documented for this variant. The VCEP PP1 thresholds of 3 or 4, 5 or 6, or at least 7 meioses across at least two families therefore cannot be evaluated.

VCEP rule

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

Evidence considered

• No affected family members, informative relatives, pedigrees, segregation results, or meiosis count is documented in the available case evidence.

Still missing

• Affected family members with phenotype information
• Variant genotypes in informative relatives
• Family pedigrees and phase information
• Count of informative meioses and number of families

Sources

Reasoning

No affected relatives or family-level segregation results are documented, so there is no evidence of lack of segregation in either one family or two or more families. The VCEP BS4 rule cannot be evaluated.

VCEP rule

Lack of segregation in affected members of one family.

Evidence considered

• No affected-family genotypes, phenotype data, pedigrees, or documented non-segregation result is available in the case evidence.

Still missing

• Affected family members and their variant genotypes
• Family-level phenotype information
• Documented non-segregation in at least one family
• Number of families with qualifying non-segregation

Sources

Reasoning

The PTEN VCEP BP2 rule requires either observation of the variant in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants. The available case evidence documents no qualifying trans observation, cis observation, phase-unknown observation, accompanying PTEN variant, or affected-proband allelic observation; BP2 cannot be assessed.

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

• ClinGen PTEN Expert Panel specification v3.2 BP2 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."
• The consolidated case evidence contains no documented qualifying co-occurring PTEN variant, phase result, or affected-proband allelic observation for NM_000314.8:c.69_73del.

Still missing

• A documented co-occurring pathogenic or likely pathogenic PTEN variant.
• Confirmed trans phase, or at least three distinct cis and/or phase-unknown observations with different pathogenic or likely pathogenic PTEN variants.
• Affected-proband and inheritance details for each qualifying observation.

Sources

Reasoning

The PTEN VCEP permits BP5 at supporting strength only when the variant is found in a case with an alternate molecular basis for disease, the other gene/disorder is highly penetrant, and the patient's personal or family history demonstrates no overlap between that disorder and PTEN. The available case evidence contains no qualifying alternate-gene diagnosis, no two qualifying cases, and no personal/family-history documentation establishing the required absence of phenotype overlap. BP5 is therefore not assessed.

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 v3.2 BP5 instructions require at least two such cases and additionally require a highly penetrant alternate gene/disorder with personal and family history demonstrating no overlap between the other gene and PTEN.
• No qualifying alternate molecular diagnosis, qualifying case series, penetrance documentation, or non-overlapping personal/family history is present in the available case evidence.

Still missing

• At least two cases carrying the variant with an alternate molecular diagnosis
• Evidence that the alternate gene/disorder is highly penetrant
• Personal and family histories showing no overlap between the alternate disorder and PTEN

Sources