PTEN c.357dup, p.(Ala120CysfsTer6)

Reasoning

NM_000314.8:c.357dup is a frameshift producing NP_000305.3:p.(Ala120CysfsTer6) / p.(A120Cfs*6). The governing PTEN decision tree covers nonsense or frameshift variants and assigns PVS1 when the variant is predicted to undergo NMD, disrupts at or 5' to p.D375 (c.1121), and the exon is present in the biologically relevant NM_000314.8 transcript. c.357 is 5' to c.1121, and this early truncating frameshift is therefore assigned full PVS1 without a named downgrade. The exact variant notations c.357dup, p.Ala120CysfsTer6, and p.A120Cfs*6 were not found in PVS1_DecisionTree_PTEN.pdf.txt; the file contains the governing generic decision tree rather than a variant-specific pre-assigned row.

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

• Case normalization: NM_000314.8:c.357dup produces NP_000305.3:p.(Ala120CysfsTer6) / p.(A120Cfs*6), and the consequence class is frameshift.
• PTEN PVS1_DecisionTree_PTEN.pdf, page 1: the nonsense/frameshift path assigns PVS1 for a variant predicted to undergo NMD with disruption at or 5' to p.D375 (c.1121) when the exon is present in biologically relevant transcript NM_000314.8.
• Exact-notation search of PVS1_DecisionTree_PTEN.pdf.txt found no c.357dup, p.Ala120CysfsTer6, or p.A120Cfs*6 row; no variant-specific pre-assigned code was therefore available in that file.

Still missing

• No exact c.357dup, p.Ala120CysfsTer6, or p.A120Cfs*6 entry was found in PVS1_DecisionTree_PTEN.pdf.txt; the generic VCEP decision tree was applied.
• The case evidence identifies the consequence and governing transcript but does not provide an independently named exon number or direct experimental NMD assay; the VCEP tree path is nevertheless resolved by the early frameshift position and transcript relevance.

Sources

Reasoning

The PTEN VCEP permits PM2 at Supporting strength when the variant is absent or present below 0.00001 (0.001%) allele frequency 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 gnomAD v2.1 and v4.1, satisfying the VCEP population 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

• ClinGen PTEN VCEP Version 3.2, PM2 rule: databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; if multiple alleles are present within any subpopulation, that subpopulation allele frequency must be <0.00002 (0.002%).
• gnomAD v2.1 all-comers query: variant absent, consistent with allele frequency 0 and therefore below 0.00001 (0.001%).
• gnomAD v4.1 all-comers query: variant absent, consistent with allele frequency 0 and therefore below 0.00001 (0.001%).

Sources

Reasoning

The VCEP PM1 rule defines critical catalytic-motif residues as 90-94, 123-130, and 166-168 of NP_000305.3. The queried frameshift starts at codon 120, which is outside all three approved intervals; vcep_materials.json contains no domain_tables entry for PTEN, and the hotspot assessment was negative.

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

• CSPEC criterion PM1: approved catalytic-motif intervals are residues 90-94, 123-130, and 166-168 (NP_000305.3).
• Variant normalization records NP_000305.3:p.(Ala120CysfsTer6), so the initiating codon is 120, outside every listed interval; vcep_materials.json has no PTEN domain_tables entry.
• Cancer Hotspots result for PTEN A120: no statistically significant hotspot found.

Sources

Reasoning

The PTEN VCEP assigns BA1 when the gnomAD filtering allele frequency is greater than 0.00056 (0.056%). The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no allele frequency above this threshold is observed and BA1 is not met.

VCEP rule

gnomAD Filtering allele frequency >0.00056 (0.056%)

Evidence considered

• ClinGen PTEN VCEP Version 3.2, BA1 rule: gnomAD filtering allele frequency >0.00056 (0.056%).
• gnomAD v2.1 all-comers query for NC_000010.10:g.89692873dup / 10-89692871-G-GT: search_status absent; no allele-frequency record was returned.
• gnomAD v4.1 all-comers query for chr10:87933114 G>GT: search_status absent; no allele-frequency record was returned.

Sources

Reasoning

The PTEN VCEP 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 gnomAD v2.1 and v4.1, so neither frequency interval is met.

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 Version 3.2, BS1 Strong rule: gnomAD filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).
• ClinGen PTEN VCEP Version 3.2, BS1 Supporting rule: allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).
• gnomAD v2.1 all-comers query: variant absent; no filtering allele frequency was reported.
• gnomAD v4.1 all-comers query: variant absent; no filtering allele frequency was reported.

Sources

Reasoning

The PTEN VCEP requires observation of the variant in the homozygous state in a healthy or PHTS-unaffected individual; one observation is sufficient only when homozygous status is confirmed, otherwise two are required. The available population records report the variant as absent from gnomAD v2.1 and v4.1 and provide no homozygous observations, so BS2 is not met.

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

• ClinGen PTEN VCEP Version 3.2, BS2 Strong rule requires a homozygous observation in a healthy or PHTS-unaffected individual; one observation requires confirmed homozygous status and two are required if status is not confirmed.
• gnomAD v2.1 all-comers query: variant absent, with no homozygote count or homozygous individual reported.
• gnomAD v4.1 all-comers query: variant absent, with no homozygote count or homozygous individual reported.

Sources

Reasoning

The available case evidence identifies NM_000314.8:c.357dup as a PTEN frameshift but provides no proband-level documentation of de novo occurrence, parental testing, maternity or paternity confirmation, or absence of family history. Therefore the PTEN VCEP PS2 rule 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

• Case evidence identifies NM_000314.8:c.357dup as a PTEN frameshift, NP_000305.3:p.(A120Cfs*6), but contains no proband-level de novo, parental-testing, maternity, paternity, or family-history data.
• No fetched paper in the case literature packet provides variant-specific clinical, segregation, or de novo evidence for c.357dup.

Still missing

• Document the affected proband and phenotype consistent with PTEN hamartoma tumor syndrome.
• Provide parental testing results and whether both maternity and paternity were confirmed.
• Document whether there is no family history of disease.

Sources

Reasoning

The PTEN VCEP specifies PS3_Moderate for a Mighell et al. 2018 Table S2 phosphatase-assay result with phosphatase activity (cumulative score) <= -1.11, provided the variant is listed as high confidence. The governing mmc2.xlsx file was searched for c.357dup, p.Ala120CysfsTer6, and p.A120Cfs*6; none was found. The file contains nearby residue-120 missense entries such as A120C, but those are not the assessed frameshift variant. Because the available governing assay table is explicitly for PTEN missense variants and supplies no result for this frameshift, PS3 cannot be evaluated from the permitted evidence.

VCEP rule

Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect on the gene or gene product. * Phosphatase activity <= -1.11 per Mighell et al. 2018, PMID: 29706350.

Evidence considered

• ClinGen PTEN VCEP v3.2 PS3 specification: PS3_Moderate uses Mighell et al. 2018 Table S2, requires a high-confidence listing, and applies when phosphatase activity is <= -1.11.
• Mighell et al. 2018 supplementary data mmc2.xlsx, Table S2 search: no row for c.357dup, p.Ala120CysfsTer6, or p.A120Cfs*6; residue-120 missense rows including A120C are different variants and were not used.
• The assessed variant is NM_000314.8:c.357dup, predicted p.(Ala120CysfsTer6)/p.(A120Cfs*6), a frameshift rather than a Table S2 missense substitution.

Still missing

• No exact entry for NM_000314.8:c.357dup, p.Ala120CysfsTer6, or p.A120Cfs*6 was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PTEN/fulltext/mmc2.xlsx.txt.
• No permitted variant-specific functional assay result for this frameshift was available to evaluate PS3.

Sources

Reasoning

The PTEN VCEP permits PS4 using either a sufficiently powered case-control result or phenotype-specificity scoring: an odds ratio >2 for a PHTS component phenotype with p<0.05 and a 95% confidence-interval lower limit >1.5, or specificity scores of 1-1.5 for Supporting, 2-3.5 for Moderate, 4-15.5 for Strong, and ≥16 for Very Strong. The available case evidence contains no odds ratio, p-value, confidence interval, proband phenotype, Cleveland Clinic score, pediatric phenotype score, or independent-proband count, so PS4 cannot be evaluated.

Evidence considered

• No case-control enrichment statistic or phenotype-specificity score was present for NM_000314.8:c.357dup.
• The available extracted publications did not mention NM_000314.8:c.357dup or NP_000305.3:p.(A120Cfs*6) and supplied no variant-specific clinical cohort evidence.

Still missing

• Case-control odds ratio, p-value, and 95% confidence interval for a PHTS component phenotype are unavailable.
• Proband phenotype data and PTEN VCEP specificity scores are unavailable.

Sources

Reasoning

The available case evidence provides no presumed de novo observation for NM_000314.8:c.357dup, no affected proband documentation, no family-history assessment, and no information on maternity or paternity confirmation. 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

• Case evidence contains variant normalization and consequence information but no clinical de novo observation or parental/family-history data.
• No fetched paper in the case literature packet provides variant-specific clinical, segregation, or de novo evidence for c.357dup.

Still missing

• Document the affected proband and phenotype consistent with PTEN hamartoma tumor syndrome.
• Provide evidence supporting presumed de novo occurrence.
• Document family history and whether maternity and paternity were confirmed.

Sources

Reasoning

The available case evidence contains no affected relatives, unaffected relatives, family structure, variant-positive or variant-negative relatives, or countable meioses for NM_000314.8:c.357dup. The PTEN VCEP PP1 co-segregation thresholds therefore cannot be evaluated.

VCEP rule

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

Evidence considered

• The case evidence bundle contains no family segregation observations or meiosis count for NM_000314.8:c.357dup.
• No fetched paper in the case literature packet provides variant-specific segregation evidence for c.357dup.

Still missing

• Provide family pedigree and clinical status of relatives.
• Provide genotype and phenotype results for informative relatives.
• Provide the number of informative meioses across families.

Sources

Reasoning

The PTEN VCEP specifies BS3_Supporting for an in vitro or in vivo study showing no damaging effect on protein function, including a Mighell et al. 2018 Table S2 phosphatase activity score > 0 for a high-confidence variant entry. The governing mmc2.xlsx file was searched for c.357dup, p.Ala120CysfsTer6, and p.A120Cfs*6; none was found. The file contains nearby residue-120 missense entries such as A120C, but those are not the assessed frameshift variant. Therefore, the permitted functional evidence does not provide a benign assay result for this frameshift, and BS3 cannot be evaluated.

VCEP rule

_In vitro_ or _in vivo_ functional study or studies showing no damaging effect on protein function. * Phosphatase activity >0 per Mighell et al. 2018, PMID: 29706350.

Evidence considered

• ClinGen PTEN VCEP v3.2 BS3 specification: BS3_Supporting uses an in vitro or in vivo study showing no damaging effect on protein function, with Mighell et al. 2018 phosphatase activity > 0 as the specified Table S2 path.
• Mighell et al. 2018 supplementary data mmc2.xlsx, Table S2 search: no row for c.357dup, p.Ala120CysfsTer6, or p.A120Cfs*6; residue-120 missense rows including A120C are different variants and were not used.
• The assessed variant is NM_000314.8:c.357dup, predicted p.(Ala120CysfsTer6)/p.(A120Cfs*6), a frameshift rather than a Table S2 missense substitution.

Still missing

• No exact entry for NM_000314.8:c.357dup, p.Ala120CysfsTer6, or p.A120Cfs*6 was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PTEN/fulltext/mmc2.xlsx.txt.
• No permitted variant-specific functional assay result demonstrating no damaging effect for this frameshift was available to evaluate BS3.

Sources

Reasoning

The available case evidence contains no affected family members tested for NM_000314.8:c.357dup and no documented lack of segregation in one or more families. The PTEN VCEP BS4 rule cannot therefore be evaluated.

VCEP rule

Lack of segregation in affected members of one family.

Evidence considered

• The case evidence bundle contains no affected-relative testing results and no family-level non-segregation observation for NM_000314.8:c.357dup.
• No fetched paper in the case literature packet provides variant-specific non-segregation evidence for c.357dup.

Still missing

• Provide family-level testing results for affected relatives.
• Document whether the variant is absent in affected members and identify the number of families involved.

Sources

Reasoning

The PTEN VCEP permits BP2 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 and/or phase unknown with different pathogenic or likely pathogenic PTEN variants. The available case evidence documents NM_000314.8:c.357dup and a single ClinVar submission classified as uncertain significance, but provides no affected-proband observations with a pathogenic/likely pathogenic PTEN variant and no cis, trans, or phase information. The criterion therefore cannot be evaluated.

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."
• Case normalization identifies the queried variant as NM_000314.8:c.357dup (NP_000305.3:p.(Ala120CysfsTer6)); the available case materials contain no cis, trans, or phase assignment and no qualifying affected-proband partner observation.
• ClinVar variation 2687567 contains one clinical-laboratory submission for NM_000314.8:c.357dup, classified as uncertain significance with no assertion criteria; it does not provide a pathogenic/likely pathogenic PTEN partner or phase information.

Still missing

• Documented affected-proband observations for NM_000314.8:c.357dup with a pathogenic or likely pathogenic PTEN variant.
• Validated cis, trans, or phase-unknown relationship for each qualifying PTEN variant pair.
• At least three qualifying cis and/or phase-unknown observations if the trans path is not established.

Sources

Reasoning

The PTEN VCEP requires a variant to be found in at least two cases with an alternate molecular basis, with the other gene/disorder considered highly penetrant and each patient's personal or family history demonstrating no overlap between the other gene and PTEN. The available evidence provides no qualifying two-case series, alternate gene diagnosis, penetrance assessment, or non-overlapping personal/family histories, so BP5 cannot be evaluated.

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

• No qualifying alternate molecular diagnosis or two-case series was documented for this variant.
• No penetrance assessment or personal/family-history comparison excluding overlap with PTEN was documented.

Still missing

• At least two cases with an alternate molecular basis for disease are unavailable.
• Evidence that the alternate gene/disorder is highly penetrant and that personal/family histories do not overlap with PTEN is unavailable.