PTEN c.387dup, p.(Arg130ThrfsTer50)

Reasoning

NM_000314.8:c.387dup, also annotated as NP_000305.3:p.(Arg130ThrfsTer50) / p.(R130Tfs*50), is a frameshift in the governing PTEN transcript NM_000314.8. The altered codon is p.Arg130, which is 5' of the PTEN-specific p.D375 (c.1121) threshold. The PTEN PVS1 decision tree assigns frameshift variants predicted to undergo NMD, with a stop codon or disruption at or 5' to p.D375 in a biologically relevant transcript, to PVS1. The ClinGen PTEN Expert Panel specification directs use of this decision tree. No named VCEP downgrade rule applies; therefore PVS1 is met at full strength, reported as very strong. Exact searches for c.387dup, p.Arg130ThrfsTer50, and p.R130Tfs*50 found no variant-specific entry in PVS1_DecisionTree_PTEN.pdf; the governing rule itself supports the call.

Rule

PTEN PVS1_DecisionTree_PTEN.pdf: frameshift, biologically relevant NM_000314.8 transcript, and premature termination at or 5' to p.D375 (c.1121) receive full PVS1; full strength is reported as very strong.

Evidence considered

• The normalized variant is NM_000314.8:c.387dup with protein consequences NP_000305.3:p.(Arg130ThrfsTer50) and p.(R130Tfs*50).
• The case evidence classifies c.387dup as a frameshift and identifies NM_000314.8 as the governing PTEN transcript.
• The PTEN PVS1 decision tree states that a frameshift with a stop codon or disruption at or 5' to p.D375 (c.1121), in a biologically relevant transcript and predicted to undergo NMD, receives PVS1.
• The disruption begins at p.Arg130, well before the p.D375 positional threshold; no specific VCEP downgrade rule applies.
• The ClinGen PTEN Expert Panel Version 3.2 specification directs use of the PTEN PVS1 decision tree for PVS1.

Still missing

• No exact c.387dup, p.Arg130ThrfsTer50, or p.R130Tfs*50 entry was found in PVS1_DecisionTree_PTEN.pdf; the PTEN-specific frameshift/NMD decision-tree rule was applied instead.

Sources

Reasoning

The governing PTEN VCEP specifies PM1 at residues 90-94, 123-130, and 166-168 of NP_000305.3, defined as catalytic motifs within a critical functional domain. The frameshift begins at Arg130, which is within the complete 123-130 motif; therefore the variant is located in a VCEP-defined critical functional region. vcep_materials.json has no PTEN domain_tables entry, so the VCEP's explicit flattened PM1 residue list is the applicable specification.

Rule

PTEN VCEP PM1: located in a mutational hotspot and/or critical, well-established functional domain; catalytic motifs include residues 90-94, 123-130, and 166-168 (NP_000305.3).

Evidence considered

• The PTEN VCEP PM1 rule defines critical catalytic motifs at residues 90-94, 123-130, and 166-168 on NP_000305.3.
• The variant protein consequence is p.(Arg130ThrfsTer50), so the affected starting residue is Arg130 and lies within the specified 123-130 interval.
• No PTEN entry is present under vcep_materials.json domain_tables; the explicit PTEN VCEP PM1 residue list was therefore checked directly and includes residue 130.

Sources

Reasoning

The ClinGen PTEN Expert Panel Version 3.2 specification permits PM2 Supporting when the variant is absent or has 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%). NM_000314.8:c.387dup is absent from gnomAD v2.1 and gnomAD v4.1, satisfying the absence requirement. The VCEP does not specify a non-cancer or exome-only source for PM2, so the default all-comers datasets were used.

Rule

Absent in population; databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population, with <0.00002 (0.002%) required within a subpopulation if multiple alleles are present.

Evidence considered

• The PTEN VCEP defines PM2 Supporting as absence or allele frequency <0.00001 (0.001%) in gnomAD, with a <0.00002 subpopulation condition when multiple alleles are present.
• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent; the observed frequency is 0, below the PTEN PM2 threshold.

Sources

Reasoning

The ClinGen PTEN Expert Panel specification defines BA1 as a gnomAD filtering allele frequency greater than 0.00056 (0.056%). NM_000314.8:c.387dup is absent from gnomAD v2.1 and gnomAD v4.1, so its observed frequency is 0 and does not meet the BA1 threshold. The VCEP does not require a non-cancer or exome-only subset for this criterion, so the default all-comers datasets were used.

Rule

gnomAD Filtering allele frequency >0.00056 (0.056%)

Evidence considered

• The PTEN VCEP Version 3.2 rule defines BA1 at gnomAD filtering allele frequency >0.00056 (0.056%).
• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent; therefore the observed allele frequency is 0.

Sources

Reasoning

The ClinGen PTEN Expert Panel specification defines 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%). NM_000314.8:c.387dup is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed frequency of 0; it therefore meets neither BS1 range. The VCEP does not require a non-cancer or exome-only subset for BS1, so the default all-comers datasets were used.

Rule

Strong: 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

• The PTEN VCEP defines BS1 Strong as 0.000043–0.00056 and BS1 Supporting as 0.0000043–0.000043 gnomAD filtering allele frequency.
• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent; the observed allele frequency is 0 and is below both BS1 ranges.

Sources

Reasoning

The PTEN VCEP specifies PS2 Strong for a de novo observation in a patient with disease and no family history when both maternity and paternity are confirmed; PS2 Very Strong requires two proven, four assumed, or one proven plus two assumed de novo observations. The available case evidence contains no documented affected proband, phenotype assessment, parental testing, maternity or paternity confirmation, or count of de novo observations for NM_000314.8:c.387dup, so PS2 cannot be assigned.

Rule

De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history; Very Strong requires two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.

Evidence considered

• The PTEN Expert Panel Version 3.2 specification assigns PS2 Strong to a de novo observation with confirmed maternity and paternity in a patient with disease and no family history.
• The same specification assigns PS2 Very Strong only for two proven, four assumed, or one proven plus two assumed de novo observations.
• The case materials provide no case-level proband, phenotype, parental-testing, family-history, or de novo documentation for NM_000314.8:c.387dup.

Still missing

• Affected proband and PTEN hamartoma tumor syndrome phenotype are not documented.
• Parental testing results, including confirmed maternity and paternity, are not documented.
• The number and evidentiary status of de novo observations are not documented.
• Family history is not documented.

Sources

Reasoning

The ClinGen PTEN Expert Panel specification permits PS4 from either a case-control result or aggregated phenotype-specific proband scores. Its case-control instruction requires an odds ratio >2 for a PHTS component phenotype, p<0.05, and a 95% confidence-interval lower limit >1.5. Its phenotype-specific scoring requires independent proband data: adults receive 1 point for Cleveland Clinic score ≥30 or 0.5 for score 25-29, and children receive 1 point for pediatric score ≥5 or 0.5 for score 4. No case-control counts, odds ratio, p-value, confidence interval, Cleveland Clinic scores, pediatric scores, or qualifying proband series are available for NM_000314.8:c.387dup. Therefore PS4 cannot be assessed; no numeric comparison is available to evaluate.

Rule

Case-control: odds ratio >2 for a PHTS component phenotype with p<0.05 and 95% confidence-interval lower limit >1.5. Alternatively, phenotype specificity scores are summed across independent probands: adults receive 1 point for Cleveland Clinic score ≥30 or 0.5 for 25-29; children receive 1 point for pediatric phenotype score ≥5 or 0.5 for score 4. PS4 strength is very strong at ≥16, strong at 4-15.5, moderate at 2-3.5, and supporting at 1-1.5.

Evidence considered

• The PTEN VCEP states: case-control PS4 may be used when odds ratio >2, p<0.05, and the 95% confidence-interval lower limit >1.5.
• The PTEN VCEP assigns PS4 strength from aggregated specificity scores: ≥16 for very strong, 4-15.5 for strong, 2-3.5 for moderate, and 1-1.5 for supporting.
• The available case evidence contains no variant-specific case-control statistics or proband phenotype scores for NM_000314.8:c.387dup.

Still missing

• Case-control counts or an odds ratio, p-value, and 95% confidence interval for this exact variant or an appropriate PHTS component phenotype.
• Independent proband-level Cleveland Clinic scores or pediatric phenotype scores sufficient to calculate the PS4 specificity score.

Sources

Reasoning

The PTEN VCEP specifies PM6 Moderate for an assumed de novo observation without confirmation of maternity and paternity in a proband with disease and no family history, PM6 Strong for two presumed de novo probands or a highly specific phenotype, and PM6 Very Strong for two proven, four assumed, or one proven plus two assumed observations. No affected proband, phenotype, family history, parental testing, or specific de novo report for NM_000314.8:c.387dup is documented in the available evidence, so PM6 cannot be assigned.

Rule

Assumed de novo without confirmation of paternity and maternity in a proband with disease and no family history; Strong requires two probands with presumed de novo occurrence or a presumed de novo highly specific phenotype; Very Strong requires two proven OR four assumed OR one proven + two assumed observations.

Evidence considered

• The PTEN Expert Panel Version 3.2 specification assigns PM6 Moderate to an assumed de novo observation without maternity and paternity confirmation in a proband with disease and no family history.
• The specification provides stronger PM6 levels for multiple presumed or proven de novo observations and for a highly specific phenotype.
• The available case materials do not document a specific de novo report or the clinical and parental details needed to apply PM6.

Still missing

• A specific de novo report for this variant is not available.
• Affected proband and disease phenotype are not documented.
• Family history is not documented.
• Maternity and paternity confirmation status is not documented.
• The number of presumed or proven de novo observations is not documented.

Sources

Reasoning

The PTEN VCEP requires co-segregation with disease in multiple affected family members and assigns PP1 Supporting for 3 or 4 meioses, Moderate for 5 or 6 meioses, and Strong for at least 7 meioses across at least two families. The available case evidence contains no affected relatives, segregation results, family structure, or meiosis count for NM_000314.8:c.387dup, so PP1 cannot be assigned.

Rule

Co-segregation with disease in multiple affected family members: Strong at >=7 meioses across at least two families, Moderate at 5 or 6 meioses, and Supporting at 3 or 4 meioses.

Evidence considered

• The PTEN Expert Panel Version 3.2 specification assigns PP1 Supporting for 3 or 4 informative meioses, Moderate for 5 or 6, and Strong for at least 7 meioses across at least two families.
• No family segregation data or informative meiosis count for NM_000314.8:c.387dup is present in the available case materials.

Still missing

• Affected family members are not documented.
• Variant status in affected and unaffected relatives is not documented.
• Family structure and informative meioses are not documented.
• The number of families and meioses is not documented.

Sources

Reasoning

The ClinGen PTEN Expert Panel specification requires observation of the variant in the homozygous state in a healthy or PHTS-unaffected individual for BS2 Strong; one observation is sufficient when homozygosity is confirmed, while two are required when it is not confirmed by parental testing. The available population records report NM_000314.8:c.387dup as absent from gnomAD v2.1 and v4.1 and provide no homozygote observations. Absence from these databases cannot establish BS2, so the criterion is not assessed.

Rule

Strong: observed in the homozygous state in a healthy or PHTS-unaffected individual, with one observation if homozygosity is confirmed and two if not confirmed; Supporting: two homozygous observations without clinical data or BS2 when BS1 is also applied.

Evidence considered

• The PTEN VCEP requires a homozygous observation in a healthy or PHTS-unaffected individual for BS2 Strong; two observations are required if homozygosity is not confirmed by parental testing.
• gnomAD v2.1 and gnomAD v4.1 report the variant as absent and therefore provide no homozygote observation.

Still missing

• A confirmed healthy or PHTS-unaffected homozygous observation, or two independent unconfirmed homozygous observations, is unavailable.

Sources

Reasoning

The PTEN VCEP specifies BS4 Supporting for lack of segregation in affected members of one family and BS4 Strong for lack of segregation in affected members of two or more families. The available case evidence contains no affected-family testing, non-segregation observation, or family count for NM_000314.8:c.387dup; therefore BS4 cannot be assigned. The specification also cautions that phenocopies and multiple pathogenic variants can mimic lack of segregation, but no family data are available to evaluate those issues.

Rule

Lack of segregation in affected members of two or more families is Strong; lack of segregation in affected members of one family is Supporting.

Evidence considered

• The PTEN Expert Panel Version 3.2 specification assigns BS4 Supporting for lack of segregation in affected members of one family and BS4 Strong for two or more families.
• The specification cautions that phenocopies and multiple pathogenic variants can confound apparent lack of segregation.
• No affected-family testing or non-segregation data for NM_000314.8:c.387dup is present in the available case materials.

Still missing

• Affected family members and their clinical status are not documented.
• Variant testing results in affected relatives are not documented.
• The number of families showing non-segregation is not documented.
• Potential phenocopies or additional pathogenic variants cannot be evaluated without family data.

Sources

Reasoning

The PTEN VCEP Version 3.2 BP2 rule requires either observation of NM_000314.8:c.387dup 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 affected-proband genotype, second PTEN variant, phase determination, or qualifying multi-observation series, so BP2 cannot be assessed.

Rule

Supporting: 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 PTEN VCEP Version 3.2 BP2 rule requires observation 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 case evidence contains no documented affected-proband second PTEN variant, phase result, or qualifying cis/phase-unknown observation series for NM_000314.8:c.387dup.

Still missing

• Affected-proband records with a second PTEN pathogenic or likely pathogenic variant are unavailable.
• Phase information for any second PTEN variant is unavailable.
• No qualifying series of at least three cis and/or phase-unknown observations with different pathogenic or likely pathogenic PTEN variants is documented.

Sources

Reasoning

The ClinGen PTEN Expert Panel permits BP5 at supporting strength only when the variant is found in a case with an alternate molecular basis for disease, at least two such cases are available, the other gene/disorder is highly penetrant, and the patient's personal or family history shows no overlap with PTEN. The available case evidence contains no alternate pathogenic molecular diagnosis, no qualifying count of cases, and no personal or family-history assessment. BP5 therefore cannot be assessed.

Rule

Variant found in a case with an alternate molecular basis for disease; the other gene/disorder must be highly penetrant, the patient's personal/family history must demonstrate no overlap with PTEN, and at least two such cases are required.

Evidence considered

• The PTEN VCEP BP5 rule requires an alternate molecular basis, a highly penetrant other gene/disorder, and no overlap between the patient's personal/family history and PTEN.
• The PTEN VCEP specifies that at least two such cases are required.
• No qualifying alternate molecular basis or phenotype/family-history documentation is available for this case.

Still missing

• At least two cases in which this exact variant co-occurs with a highly penetrant alternate molecular diagnosis.
• Documentation that each patient's personal and family history has no overlap with PTEN-related disease.

Sources