PTEN c.758_760dup, p.(Ile253dup)

Reasoning

The governing ClinGen PTEN VCEP v3.2 applies PM2 at supporting strength when a variant is absent or has gnomAD or another large-population allele frequency below 0.00001 (0.001%); if multiple alleles are present in a subpopulation, that subpopulation frequency must be below 0.00002 (0.002%). NM_000314.8:c.758_760dup is absent from gnomAD v2.1 and v4.1 and from the available non-cancer subsets, satisfying the absence requirement.

Rule

PTEN VCEP v3.2: PM2 supporting if absent or present at <0.00001 (0.001%) allele frequency; if multiple alleles occur in a subpopulation, that subpopulation frequency must be <0.00002 (0.002%).

Evidence considered

• ClinGen PTEN VCEP v3.2 specifies PM2 supporting for absence or allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; when multiple alleles are present in a subpopulation, that subpopulation frequency must be <0.00002 (0.002%).
• The variant is absent from gnomAD v2.1 and v4.1, as well as gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer, so the PTEN PM2 absence criterion is met at supporting strength.

Sources

Reasoning

The PTEN VCEP defines PM1 at Moderate strength for a mutational hotspot or a critical, well-established functional domain, specifically including catalytic-motif residues 90-94, 123-130, and 166-168 on NP_000305.3. The duplicated residue is Ile253, outside every listed catalytic interval. The case hotspot search found no statistically significant PTEN I253 hotspot. vcep_materials.json has no domain_tables entry for PTEN, so there is no additional authoritative domain list to check.

Rule

Located in a mutational hotspot and/or critical and well-established functional domain; PTEN VCEP defines catalytic motifs at residues 90-94, 123-130, and 166-168, with Moderate strength.

Evidence considered

• The PTEN VCEP PM1 rule includes catalytic-motif residues 90-94, 123-130, and 166-168 as critical functional regions.
• The variant affects residue 253, which is outside all three VCEP-defined catalytic intervals.
• The PTEN I253 hotspot query returned no statistically significant hotspot result.
• No PTEN domain_tables entry is present in vcep_materials.json; therefore the VCEP catalytic intervals are the complete applicable domain specification available for this case.

Sources

Reasoning

PM4 is not met under the PTEN CSPEC. The variant is an in-frame insertion of one isoleucine at residue 253, but the governing rule applies to in-frame insertions or deletions impacting a specified catalytic motif or to variants causing protein extension. Residue 253 is outside the PTEN catalytic motifs specified by the CSPEC (residues 90-94, 123-130, and 166-168), and p.(Ile253dup) is not a protein extension. No repeat-region evidence changes this rule-based conclusion.

Rule

PTEN CSPEC PM4: catalytic-motif in-frame indel or protein extension

Evidence considered

• The case normalization identifies p.(Ile253dup), an in-frame one-residue insertion at PTEN residue 253.
• PTEN CSPEC PM4 requires an in-frame insertion or deletion affecting a specified catalytic motif, or a variant causing protein extension; the listed catalytic motifs are residues 90-94, 123-130, and 166-168.
• Residue 253 is not within any of the PTEN catalytic motifs listed in the governing CSPEC rule, and p.(Ile253dup) is not a protein extension.

Sources

Reasoning

The governing ClinGen PTEN VCEP v3.2 specifies BA1 when gnomAD filtering allele frequency is greater than 0.00056 (0.056%). NM_000314.8:c.758_760dup is absent from gnomAD v2.1 and v4.1, including the available non-cancer cohort results, so no allele frequency meets or exceeds the BA1 threshold.

Rule

PTEN VCEP v3.2: BA1 stand-alone if gnomAD filtering allele frequency >0.00056 (0.056%).

Evidence considered

• ClinGen PTEN VCEP v3.2 defines BA1 as gnomAD filtering allele frequency >0.00056 (0.056%).
• The variant is absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, and gnomAD v3.1 non-cancer; therefore no observed allele frequency reaches the BA1 threshold.

Sources

Reasoning

The governing ClinGen PTEN VCEP v3.2 defines BS1 as a gnomAD filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%), with a supporting-level range from 0.0000043 to 0.000043. NM_000314.8:c.758_760dup is absent from gnomAD v2.1 and v4.1, including the available non-cancer cohort results, so BS1 is not met at either strength.

Rule

PTEN VCEP v3.2: BS1 strong for gnomAD filtering allele frequency 0.000043 to <0.00056; supporting for 0.0000043 to <0.000043.

Evidence considered

• ClinGen PTEN VCEP v3.2 defines BS1 strong as 0.000043 to <0.00056 and BS1 supporting as 0.0000043 to <0.000043 allele frequency.
• The variant is absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, and gnomAD v3.1 non-cancer; no BS1-range allele frequency is observed.

Sources

Reasoning

The PTEN VCEP requires a proven de novo observation with confirmed maternity and paternity, disease in the patient, and no family history for PS2 at strong strength; the available case evidence contains no proband phenotype, parental testing, maternity/paternity confirmation, or family-history data.

Rule

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

Evidence considered

• The PTEN VCEP PS2 rule requires de novo occurrence with both maternity and paternity confirmed in a patient with the disease and no family history.
• No case-level proband, parental, or family-history evidence was available to evaluate those requirements.

Still missing

• Proband diagnosis and phenotype consistent with PTEN hamartoma tumor syndrome are not documented.
• Parental testing results are not documented.
• Maternity and paternity confirmation are not documented.
• Family history and absence of a relevant family history are not documented.

Sources

Reasoning

The PTEN VCEP specifies PS3_Moderate for Mighell et al. 2018 Table S2 only when the queried variant is present as a high-confidence missense assay result (High_conf=True) with Cum_score <= -1.11. The governing mmc2 full text was searched for c.758_760dup, p.Ile253dup, and p.I253dup, with no matching entry. The case variant is an in-frame duplication producing p.(Ile253dup), not a missense substitution, and no variant-specific functional assay evidence or qualifying splicing assay is available in the case materials; therefore PS3 cannot be assigned.

Rule

PS3_Moderate requires a high-confidence Mighell et al. 2018 Table S2 result with Cum_score <= -1.11; other qualifying functional assays may support PS3 at the specified strength, but none is available for this variant.

Evidence considered

• The ClinGen PTEN VCEP Version 3.2 specification permits PS3_Moderate for Mighell et al. 2018 Table S2 only when the variant is listed as High_conf=True and has Cum_score <= -1.11.
• The full converted mmc2.xlsx text was searched under all requested notations—c.758_760dup, p.Ile253dup, and p.I253dup—and none was found.
• Case normalization identifies NM_000314.8:c.758_760dup as NP_000305.3:p.(Ile253dup), an in-frame duplication; no qualifying variant-specific functional or splicing assay result was present.

Still missing

• No matching c.758_760dup, p.Ile253dup, or p.I253dup entry was found in the governing VCEP file /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/PTEN/fulltext/mmc2.xlsx.txt.
• No variant-specific functional study demonstrating impaired phosphatase activity, abnormal cellular function, or altered splicing was available in the reviewed case materials.

Sources

Reasoning

The PTEN VCEP specifies PS4 for a sufficiently powered case-control study with odds ratio >2 for a PHTS component phenotype, p<0.05, and a 95% confidence-interval lower limit >1.5, or for phenotype-specificity scores: very strong at >=16, strong at 4-15.5, moderate at 2-3.5, and supporting at 1-1.5. The case evidence contains no case-control study, proband-level phenotype information, family history, specificity score, or qualifying PS4 observations for NM_000314.8:c.758_760dup, so PS4 cannot be assessed. No numeric comparison is applicable because no PS4 metric was reported.

Rule

PTEN EP Commentary: This criterion is unlikely to be used in this manner for a condition as rare as PHTS. However, if sufficiently powered, a case-control study finding an odds ratio >2 for a PHTS component phenotype with p<0.05 and 95% confidence interval with lower limit >1.5, this criteria may be applied. Use 2: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Phenotype specificity scores are added across independent probands. PS4_Very Strong: Probands with specificity score >=16. 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.

Evidence considered

• The PTEN Expert Panel specification states that a sufficiently powered case-control study may support PS4 when odds ratio >2, p<0.05, and the 95% confidence-interval lower limit >1.5.
• The PTEN Expert Panel specification assigns PS4 strength from phenotype-specificity scores: >=16 very strong, 4-15.5 strong, 2-3.5 moderate, and 1-1.5 supporting.
• The available case evidence reports no variant-specific phenotype cohort, case-control analysis, proband specificity score, or family-history data.

Still missing

• Case-control counts or odds ratio, p-value, and 95% confidence interval are unavailable.
• Independent proband phenotype-specificity scores and supporting phenotype or family-history details are unavailable.

Sources

Reasoning

The PTEN VCEP permits PM6 for an assumed de novo occurrence without confirmed maternity and paternity, with strength depending on the number of occurrences and phenotype specificity; no de novo observations, proband phenotype, family history, or parental testing data are documented for this case.

Rule

Assumed de novo, but without confirmation of paternity and maternity, in a proband with the disease and no family history; higher strengths require specified counts of proven or assumed de novo observations.

Evidence considered

• The PTEN VCEP PM6 rule defines assumed de novo evidence without confirmed maternity and paternity and scales strength by the number of proven or assumed observations.
• No case-level de novo observations or supporting clinical and parental data were available.

Still missing

• At least one case with assumed or proven de novo status is not documented.
• Proband disease phenotype and phenotype specificity are not documented.
• Family-history status is not documented.
• The number of independent de novo observations cannot be determined.

Sources

Reasoning

The PTEN VCEP requires co-segregation with disease in multiple affected family members and assigns supporting strength for 3 or 4 meioses, moderate for 5 or 6, and strong for at least 7 meioses across at least two families; no affected relatives, segregation results, or meioses are documented.

Rule

Co-segregation with disease in multiple affected family members; supporting requires 3 or 4 meioses, moderate requires 5 or 6, and strong requires at least 7 meioses across at least two families.

Evidence considered

• The PTEN VCEP PP1 rule requires 3 or 4 meioses for supporting, 5 or 6 for moderate, and at least 7 meioses across at least two families for strong evidence.
• No family segregation data or informative meioses were available for this variant.

Still missing

• Affected family members are not identified.
• Variant genotypes and phenotypes in relatives are not documented.
• The number of informative meioses is not documented.
• Independent families represented by the segregation data are not documented.

Sources

Reasoning

The governing ClinGen PTEN VCEP v3.2 requires a confirmed homozygous observation in a healthy or PHTS-unaffected individual for BS2 strong, or two homozygous observations without clinical data; if BS1 is also applied, the criterion is supporting. The available gnomAD results report the variant as absent and provide no homozygote observations or genotype-count evidence, so BS2 cannot be assessed.

Rule

PTEN VCEP v3.2: BS2 strong requires a confirmed homozygous observation in a healthy or PHTS-unaffected individual, or two unconfirmed homozygous observations; apply supporting if BS1 is also applied.

Evidence considered

• ClinGen PTEN VCEP v3.2 requires one confirmed homozygous observation in a healthy or PHTS-unaffected individual for BS2 strong, or two homozygous observations without clinical data; BS2 is supporting if BS1 is also applied.
• The variant is absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, and gnomAD v3.1 non-cancer, and no homozygote or genotype-count evidence is reported.

Still missing

• No confirmed homozygous observation or genotype-count evidence in a healthy or PHTS-unaffected individual was available.

Sources

Reasoning

The PTEN VCEP specifies BS3_Supporting for Mighell et al. 2018 phosphatase activity when the relevant result is >0, while stronger BS3 requires a well-established functional study showing no damaging effect. The governing mmc2 full text was searched for c.758_760dup, p.Ile253dup, and p.I253dup, with no matching entry. Because the case variant is an in-frame duplication rather than a tested missense substitution and no variant-specific benign functional or splicing assay result is available, BS3 cannot be assigned.

Rule

BS3_Supporting requires Mighell et al. 2018 phosphatase activity >0 for the variant; stronger BS3 requires well-established functional evidence showing no damaging effect, and neither is available here.

Evidence considered

• The ClinGen PTEN VCEP Version 3.2 specification permits BS3_Supporting for Mighell et al. 2018 phosphatase activity >0 and reserves stronger BS3 for well-established functional evidence showing no damaging effect.
• The full converted mmc2.xlsx text was searched under all requested notations—c.758_760dup, p.Ile253dup, and p.I253dup—and none was found.
• Case normalization identifies NM_000314.8:c.758_760dup as NP_000305.3:p.(Ile253dup), an in-frame duplication; no qualifying variant-specific benign functional or splicing assay result was present.

Still missing

• No matching c.758_760dup, p.Ile253dup, or p.I253dup entry was found in the governing VCEP file /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/PTEN/fulltext/mmc2.xlsx.txt.
• No variant-specific functional study demonstrating preserved phosphatase activity, normal cellular function, or absence of splicing impact was available in the reviewed case materials.

Sources

Reasoning

The PTEN VCEP applies BS4 supporting for lack of segregation in one family and strong for lack of segregation in two or more families, while cautioning that phenocopies and multiple pathogenic variants can confound interpretation; no affected-family testing or non-segregation data are documented.

Rule

Lack of segregation in affected members of one family supports BS4; lack of segregation in affected members of two or more families supports BS4 at strong strength.

Evidence considered

• The PTEN VCEP BS4 rule requires lack of segregation in one family for supporting or two or more families for strong evidence.
• No affected-family testing, non-segregation observations, or confounder assessment was available.

Still missing

• Families with affected members tested for the variant are not identified.
• Variant-negative affected relatives or other non-segregation observations are not documented.
• Phenocopy and alternative pathogenic-variant assessment is not documented.

Sources

Reasoning

The PTEN VCEP Version 3.2 permits BP2 at supporting strength when the variant is observed in trans with a pathogenic or likely pathogenic PTEN variant, or when there are at least three observations in cis or phase unknown with different pathogenic or likely pathogenic PTEN variants. The available case evidence documents NM_000314.8:c.758_760dup as absent from ClinVar and population resources but provides no affected-proband observation, paired PTEN variant, phase determination, cis/trans result, or qualifying series of three phase-unknown/cis observations. BP2 therefore cannot be assessed from the available evidence.

Rule

BP2 Supporting 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/likely pathogenic PTEN variants.

Evidence considered

• The PTEN VCEP Version 3.2 specifies BP2 Supporting for the variant observed in trans with a pathogenic or likely pathogenic PTEN variant.
• The same PTEN VCEP specification allows BP2 for at least three observations in cis or phase unknown with different pathogenic or likely pathogenic PTEN variants.
• No qualifying phase, affected-proband, family, or paired-variant observation is documented for this case.

Still missing

• Documented affected-proband or family observations pairing c.758_760dup with a pathogenic or likely pathogenic PTEN variant.
• Experimental or familial phase evidence establishing the variants are in trans, or at least three qualifying cis/phase-unknown observations with different pathogenic or likely pathogenic PTEN variants.

Sources

Reasoning

The PTEN Expert Panel permits BP5 at supporting strength only when the variant is found in at least two cases with an alternate molecular basis, the other gene or disorder is highly penetrant, and the patient's personal or family history shows no overlap between that disorder and PTEN. The case evidence contains no alternate molecular diagnosis, qualifying cases, penetrance assessment, or non-overlapping personal or family history, so BP5 cannot be assessed.

Rule

PTEN EP Specifications: 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.

Evidence considered

• The PTEN Expert Panel requires at least two cases for BP5 and requires the alternate gene or disorder to be highly penetrant with no overlap between the patient's personal or family history and PTEN.
• The available case evidence contains no alternate molecular diagnosis or qualifying clinical-history information.

Still missing

• At least two variant-positive cases with an alternate molecular basis are unavailable.
• Evidence that the alternate disorder is highly penetrant and has no phenotype overlap with PTEN is unavailable.

Sources