PTEN c.521del, p.(Tyr174LeufsTer9)

Reasoning

PTEN VCEP PVS1_DecisionTree_PTEN.pdf assigns PVS1 to a nonsense or frameshift variant predicted to undergo NMD when the stop codon or disruption is at or 5' to p.D375 (c.1121) in the biologically relevant transcript NM_000314.8. NM_000314.8:c.521del is a frameshift producing NP_000305.3:p.(Tyr174LeufsTer9), well 5' of c.1121, so it meets the full-strength PVS1 branch. No exact c.521del, p.Tyr174LeufsTer9, or p.Y174Lfs*9 row appears in the searched decision-tree text; the governing general rule is directly applicable.

Rule

PTEN VCEP PVS1 decision tree: frameshift with disruption at or 5′ to p.D375/c.1121 in NM_000314.8 is PVS1.

Evidence considered

• The PTEN Expert Panel framework identifies NM_000314.8 as the preferred biologically relevant transcript and directs use of the PTEN PVS1 decision tree.
• The PTEN PVS1 decision tree assigns PVS1 when a nonsense or frameshift disruption at or 5′ to p.D375/c.1121 is predicted to undergo NMD in the biologically relevant transcript.
• The case variant is NM_000314.8:c.521del, a frameshift encoding NP_000305.3:p.(Tyr174LeufsTer9), which is upstream of c.1121 and therefore falls within the decision-tree full-strength branch.

Still missing

• No exact c.521del, p.Tyr174LeufsTer9, or p.Y174Lfs*9 entry was found in PVS1_DecisionTree_PTEN.pdf.txt; the file provides the governing general frameshift rule rather than variant-specific rows.

Sources

Reasoning

The ClinGen PTEN Expert Panel specifies PM2 at supporting strength when the variant is present at an allele frequency below 0.00001 (0.001%) in gnomAD or another large sequenced population, with a subpopulation frequency below 0.00002 (0.002%) if multiple alleles are present. NM_000314.8:c.521del is absent from gnomAD v2.1 and v4.1 and is also absent from the available gnomAD v2.1 non-cancer and v3.1 non-cancer records; therefore its observed allele frequency is 0 in each reported dataset and satisfies the PTEN PM2 threshold.

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

• PTEN VCEP v3.2 specifies PM2 supporting for 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%).
• gnomAD v2.1 reports the variant as absent, corresponding to observed allele frequency 0 in that dataset.
• gnomAD v4.1 reports the variant as absent, corresponding to observed allele frequency 0 in that dataset.
• The available gnomAD v2.1 non-cancer and v3.1 non-cancer records also report the variant as absent.

Sources

Reasoning

The ClinGen PTEN Expert Panel specifies BA1 when the gnomAD filtering allele frequency is greater than 0.00056 (0.056%). NM_000314.8:c.521del is absent from gnomAD v2.1 and gnomAD v4.1, with no observed allele frequency approaching the BA1 threshold. The variant is also absent from the available non-cancer subsets.

Rule

gnomAD Filtering allele frequency >0.00056 (0.056%)

Evidence considered

• PTEN VCEP v3.2 defines BA1 as gnomAD filtering allele frequency >0.00056 (0.056%).
• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• The available gnomAD v2.1 non-cancer and v3.1 non-cancer records also report the variant as absent.

Sources

Reasoning

The ClinGen PTEN Expert Panel specifies BS1 at strong strength for a gnomAD filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%), and BS1 supporting for 0.0000043 (0.00043%) up to 0.000043 (0.0043%). NM_000314.8:c.521del is absent from gnomAD v2.1 and gnomAD v4.1, so no allele frequency meets either BS1 interval. The variant is likewise absent from the available non-cancer subsets.

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

• PTEN VCEP v3.2 defines BS1 strong as filtering allele frequency 0.000043–0.00056 and BS1 supporting as 0.0000043–0.000043.
• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• The available gnomAD v2.1 non-cancer and v3.1 non-cancer records also report the variant as absent.

Sources

Reasoning

The PTEN Expert Panel specification requires a de novo observation in a patient with disease and no family history for PS2, with both maternity and paternity confirmed for strong evidence. The available case evidence contains no proband phenotype or diagnosis, parental testing results, maternity or paternity confirmation, or family-history information, so PS2 cannot be assessed.

Rule

De novo observation in a patient with the disease and no family history, with both maternity and paternity confirmed; PTEN PS2 Very Strong requires two proven, four assumed, or one proven plus two assumed de novo observations.

Evidence considered

• ClinGen PTEN Expert Panel Version 3.2 specifies PS2 Strong for a de novo observation in a patient with disease and no family history when both maternity and paternity are confirmed.
• No proband diagnosis or phenotype, parental genotype results, maternity/paternity confirmation, or family-history data are available for this case.

Still missing

• Document the proband's PTEN hamartoma tumor syndrome diagnosis and phenotype.
• Provide variant testing results for both biological parents, including maternity and paternity confirmation.
• Provide the proband's family history and whether the disease was absent in the parents and other relevant relatives.

Sources

Reasoning

The PTEN VCEP specification governs PS3 and identifies Mighell et al. 2018 (PMID:29706350) Table S2 as a PS3_Moderate phosphatase-activity source only for missense variants listed with a high-confidence result and Cum_score <= -1.11. The queried variant, NM_000314.8:c.521del, produces p.(Tyr174LeufsTer9)/p.(Y174Lfs*9) and is a frameshift, not a missense variant. The governing mmc2.xlsx file was searched for c.521del, p.Tyr174LeufsTer9, and p.Y174Lfs*9; no entry was found. The available functional papers were also checked through their extracted findings, and neither PMID:11237521 nor PMID:17218262 mentions this variant or reports a variant-specific functional assay. Therefore no applicable validated assay result supports PS3 for this variant.

Rule

PTEN VCEP PS3: PS3_Moderate requires Mighell et al. 2018 Table S2 evidence for a listed high-confidence missense variant with Cum_score <= -1.11; PS3_Supporting requires applicable functional evidence showing phosphatase activity <50% of wild type or another abnormal functional assay.

Evidence considered

• The PTEN VCEP PS3 specification permits PS3_Moderate for Mighell et al. 2018 Table S2 only when the missense variant is listed as high confidence and has Cum_score <= -1.11.
• NM_000314.8:c.521del is a frameshift producing p.(Tyr174LeufsTer9)/p.(Y174Lfs*9), so the missense-only mmc2 assay table is not applicable.
• Searches of mmc2.xlsx for c.521del, p.Tyr174LeufsTer9, and p.Y174Lfs*9 found no entry.
• PMID:11237521 and PMID:17218262 do not mention the queried variant and provide no variant-specific functional assay result.

Still missing

• No applicable variant-specific functional assay result was identified for the frameshift NM_000314.8:c.521del.
• mmc2.xlsx was searched for c.521del, p.Tyr174LeufsTer9, and p.Y174Lfs*9; no entry was found.
• The governing mmc2.xlsx specification does not define PS3 calibration for this frameshift variant type.

Sources

Reasoning

The PTEN Expert Panel framework permits PS4 from a case-control study showing odds ratio >2 for a PHTS component phenotype with p<0.05 and a 95% confidence-interval lower limit >1.5, or from phenotype-specificity scores accumulated across independent probands: Very Strong at >=16, Strong at 4-15.5, Moderate at 2-3.5, and Supporting at 1-1.5. The available case evidence contains no case-control counts, odds ratio, p-value, confidence interval, Cleveland Clinic scores, pediatric phenotype scores, or independent proband series for NM_000314.8:c.521del. The two fetched publications do not mention this variant, and the PTEN specification states that PS4 cannot be combined with PP4. Therefore PS4 cannot be adjudicated from the available evidence; no numeric comparison is applicable.

Rule

PTEN PS4: case-control OR >2 with p<0.05 and 95% CI lower limit >1.5; alternatively, phenotype-specificity score >=16 (Very Strong), 4-15.5 (Strong), 2-3.5 (Moderate), or 1-1.5 (Supporting). PS4 may not be combined with PP4.

Evidence considered

• The PTEN Expert Panel source states that a case-control PS4 analysis may use odds ratio >2, p<0.05, and a 95% confidence-interval lower limit >1.5; its phenotype-specificity thresholds are >=16 for Very Strong, 4-15.5 for Strong, 2-3.5 for Moderate, and 1-1.5 for Supporting.
• No variant-specific case-control data, phenotype-specificity score, or independent proband series for NM_000314.8:c.521del is present in the reviewed evidence.
• The reviewed full-text publications do not mention c.521del or p.(Y174Lfs*9).

Still missing

• Variant-specific case-control counts or a sufficiently powered affected-versus-control enrichment analysis.
• Variant-specific Cleveland Clinic or pediatric phenotype scores from independent probands.

Sources

Reasoning

The governing PTEN VCEP Version 3.2 assigns PM1 at moderate strength for a variant located in a mutational hotspot and/or critical, well-established functional domain, and defines catalytic motifs at residues 90-94, 123-130, and 166-168. The frameshift begins at Tyr174, outside those listed catalytic motifs. vcep_materials.json has no domain_tables entry for PTEN, so there is no additional authoritative domain-table interval to check. The collected Cancer Hotspots result reports PTEN Y174 as a statistically significant hotspot, but that source has no corresponding key in source_registry.json and its row extraction is partial; therefore the hotspot evidence cannot be cited under the required evidence_refs constraint and PM1 is not assessed.

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 Version 3.2 PM1 rule defines moderate evidence for a mutational hotspot or critical functional domain and lists catalytic motifs at residues 90-94, 123-130, and 166-168.
• The Cancer Hotspots result for PTEN Y174 states that the variant lies in a statistically significant hotspot; the source record warns that the row extraction was partial and provides a screenshot for confirmation.
• vcep_materials.json contains no domain_tables entry for PTEN; the explicit VCEP catalytic-motif intervals were therefore checked, and residue 174 is outside all three intervals.

Still missing

• The Cancer Hotspots Y174 row was only partially parsed and lacks a corresponding source_registry key; confirm the screenshot and register the source before applying PM1.

Sources

Reasoning

The PTEN Expert Panel specification permits PM6 for an assumed de novo variant in a proband with disease and no family history when maternity and paternity are not confirmed; stronger levels require multiple qualifying observations or a highly specific phenotype. The available case evidence contains no proband diagnosis or phenotype, parental testing, family history, or independent de novo observations, so PM6 cannot be assessed.

Rule

Assumed de novo in a proband with disease and no family history without confirmation of maternity and paternity; PTEN PM6 Strong requires two presumed de novo probands or one presumed de novo observation with a highly specific phenotype, and PM6 Very Strong requires two proven, four assumed, or one proven plus two assumed observations.

Evidence considered

• ClinGen PTEN Expert Panel Version 3.2 specifies PM6 Moderate for an assumed de novo observation in a proband with disease and no family history without confirmed maternity and paternity; two such probands or a highly specific phenotype may support PM6 Strong.
• No qualifying proband, parental, family-history, phenotype-specificity, or recurrence-count information is available for this case.

Still missing

• Document the proband's disease diagnosis and phenotype specificity.
• Document testing of both biological parents and whether the variant was absent in each parent.
• Document absence of family history and identify any additional independent assumed or proven de novo observations.

Sources

Reasoning

The PTEN Expert Panel specification requires co-segregation with disease in multiple affected family members and at least 3 meioses for PP1 Supporting, 5 or 6 meioses for PP1 Moderate, or at least 7 meioses across at least two families for PP1 Strong. The available case evidence contains no affected relatives, genotype-phenotype segregation observations, family structure, or meiosis count, so PP1 cannot be assessed.

Rule

Co-segregation with disease in multiple affected family members: 3 or 4 meioses for PP1 Supporting, 5 or 6 for PP1 Moderate, and at least 7 across at least two families for PP1 Strong.

Evidence considered

• ClinGen PTEN Expert Panel Version 3.2 requires 3 or 4 observed meioses for PP1 Supporting, 5 or 6 for PP1 Moderate, and at least 7 across at least two families for PP1 Strong.
• No family segregation, informative meiosis, affected-relative, or independent-family data are available for this case.

Still missing

• Provide pedigrees and clinical status for affected and unaffected relatives.
• Provide variant genotypes for informative relatives and phenotype data supporting or refuting co-segregation.
• Document the number of informative meioses and the number of independent families.

Sources

Reasoning

The PTEN VCEP requires observation of the variant in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observation, genotype count, or individual-level homozygote evidence is provided in the available population records; absence from gnomAD cannot establish BS2.

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

• PTEN VCEP v3.2 requires a homozygous observation in a healthy or PHTS-unaffected individual; two observations are required when homozygous status is not confirmed by parental testing.
• gnomAD v2.1 and v4.1 report the variant as absent and provide no homozygote observation.
• Absence from a population database is not evidence that a healthy individual was homozygous for the variant.

Still missing

• Confirmed homozygous observation in a healthy or PHTS-unaffected individual, or two unconfirmed homozygous observations, is unavailable.

Sources

Reasoning

The PTEN VCEP specification governs BS3 and defines BS3_Supporting using Mighell et al. 2018 phosphatase activity >0, but the governing mmc2.xlsx assay table is specified for PTEN missense variants. The queried NM_000314.8:c.521del variant is a frameshift producing p.(Tyr174LeufsTer9)/p.(Y174Lfs*9), and searches of mmc2.xlsx for c.521del, p.Tyr174LeufsTer9, and p.Y174Lfs*9 found no entry. The extracted findings for PMID:11237521 and PMID:17218262 likewise contain no mention of this variant and no variant-specific benign functional result. Thus there is no applicable assay demonstrating no damaging effect for BS3.

Rule

PTEN VCEP BS3: BS3_Strong requires a well-established functional study showing no damaging effect; BS3_Supporting includes Mighell et al. 2018 phosphatase activity >0, when applicable.

Evidence considered

• The PTEN VCEP BS3 specification defines BS3_Supporting for Mighell et al. 2018 phosphatase activity >0, within the specified missense assay dataset.
• NM_000314.8:c.521del is a frameshift producing p.(Tyr174LeufsTer9)/p.(Y174Lfs*9), and no matching entry was found in mmc2.xlsx under any requested notation.
• PMID:11237521 and PMID:17218262 do not mention the queried variant and provide no variant-specific benign functional assay result.

Still missing

• No applicable variant-specific functional assay demonstrating preserved PTEN function was identified.
• mmc2.xlsx was searched for c.521del, p.Tyr174LeufsTer9, and p.Y174Lfs*9; no entry was found.
• The governing mmc2.xlsx specification does not define BS3 calibration for this frameshift variant type.

Sources

Reasoning

The PTEN Expert Panel specification defines BS4 Supporting as lack of segregation in one family and BS4 Strong as lack of segregation in two or more families, with caution because phenocopies and multiple pathogenic variants can confound interpretation. The available case evidence contains no affected relatives, family segregation results, or family count, so BS4 cannot be assessed.

Rule

Lack of segregation in affected members of one family supports BS4 Supporting; lack of segregation in affected members of two or more families supports BS4 Strong.

Evidence considered

• ClinGen PTEN Expert Panel Version 3.2 specifies BS4 Supporting for lack of segregation in one family and BS4 Strong for lack of segregation in two or more families, with caution for phenocopies and multiple pathogenic variants.
• No non-segregation observations, affected-relative testing, family segregation results, or independent-family count are available for this case.

Still missing

• Provide pedigrees and clinical status for affected relatives tested for the variant.
• Provide genotype results demonstrating non-segregation in affected relatives and relevant alternative diagnoses or phenocopy assessment.
• Document whether the observations involve one family or at least two independent families.

Sources

Reasoning

The PTEN VCEP permits BP2 at supporting strength when NM_000314.8:c.521del is observed in trans with a pathogenic or likely pathogenic PTEN variant, or when at least three observations place it in cis or phase-unknown with different pathogenic or likely pathogenic PTEN variants. The available case evidence contains no affected-proband observation, second PTEN variant, parental or offspring testing, or cis/trans phase information, so BP2 cannot be assessed.

Evidence considered

• The governing PTEN VCEP rule allows BP2 for one observation in trans with a pathogenic or likely pathogenic PTEN variant.
• The governing PTEN VCEP rule also allows BP2 for at least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants.
• The case materials provide no reportable phase, affected-proband, parental, offspring, or second-variant observation for NM_000314.8:c.521del.

Still missing

• A documented affected-proband or family observation containing NM_000314.8:c.521del and another pathogenic or likely pathogenic PTEN variant is needed.
• The second variant's pathogenicity and cis/trans or phase-unknown relationship must be established; three distinct cis or phase-unknown observations are required if trans is not demonstrated.

Sources

Reasoning

The PTEN Expert Panel permits BP5 when the variant is found in a case with an alternate molecular basis, but requires at least two such cases, a highly penetrant alternate gene/disorder, and personal or family history showing no overlap with PTEN. The available evidence contains no such cases, alternate pathogenic molecular diagnoses, or non-overlapping clinical histories. Therefore BP5 cannot be adjudicated. No numeric BP5 threshold or comparison is specified by the PTEN rule, so no inequality is applicable.

Rule

BP5 Supporting: variant found in a case with an alternate molecular basis for disease; PTEN requires at least two cases, a highly penetrant alternate gene/disorder, and no personal/family-history overlap with PTEN.

Evidence considered

• The PTEN Expert Panel BP5 rule requires at least two cases, a highly penetrant alternate gene/disorder, and personal/family history demonstrating no overlap between the alternate disorder and PTEN.
• No qualifying alternate molecular diagnoses or corresponding clinical histories are documented for this variant.

Still missing

• At least two cases with the variant and an independently established alternate molecular diagnosis.
• Evidence that each alternate disorder is highly penetrant and that the personal/family history does not overlap with PTEN.

Sources