PTEN c.387_388del , p.(Arg130AsnfsTer49)

PS3 PS3 requires variant-specific functional assay evidence. No enzyme-activity, RNA, splicing, or cellular studies of this exact variant were available, and the PTEN saturation-mutagenesis assay covers missense variants only, so it does not apply to this frameshift. The variant's loss-of-function effect is instead captured by PVS1. Details ▾Hide ▴

Reasoning

No variant-specific functional assay evidence exists in the case bundle for NM_000314.8:c.387_388del (p.(Arg130AsnfsTer49)), a 2-bp frameshift deletion. The governing ClinGen PTEN VCEP v3.2 (CSPEC, precedence rank 1) defines PS3_Moderate as Mighell et al. 2018 (PMID: 29706350) cumulative fitness score <= -1.11 and PS3_Strong as RNA/mini-gene/other assay showing splicing impact, but the Mighell saturation-mutagenesis assay (vcep_mmc2, Table S2) covers missense variants only (index.txt: types=missense; lookup by one-/three-letter amino-acid codes), so no Cum_score entry exists for a frameshift. No RNA, mini-gene, or splicing functional assay, and no in vitro cellular or transgenic-model study of this variant, are present. OncoKB's curated 'Likely Loss-of-function' biological-effect label is a variant-consequence-based curation, not a validated functional study, and per policy a criterion may not be inferred from another source's final classification; it was therefore not used. The two available full-text papers (PMID 11237521, 17218262) are gene-level PTEN biology papers that do not mention c.387_388del/p.R130Nfs*49 and cannot support variant-specific functional evidence. PS3 is not assessed due to absence of applicable functional data; the variant's truncating consequence is instead addressed by PVS1 via the PTEN decision tree (predicted NMD, 5' of p.D375).

Rule

PTEN VCEP v3.2 PS3: Strong = well-established in vitro/in vivo functional studies supportive of damaging effect, RNA/mini-gene/other assay shows impact on splicing; Moderate = phosphatase activity <= -1.11 per Mighell et al. 2018, PMID: 29706350; Supporting = phosphatase activity <50% of wild-type or abnormal in vitro cellular assay / transgenic model phenotype different from wild type not meeting PS3_Moderate.

Still missing

No Mighell et al. 2018 (PMID: 29706350) saturation-mutagenesis Cum_score is available or applicable: assay covers missense variants only
and this variant is a 2-bp frameshift deletion (p.R130Nfs*49).
No RNA
mini-gene
or splicing functional assay result for c.387_388del (PS3_Strong requires demonstrated splicing impact).
No in vitro cellular assay or transgenic model functional data for this variant (<50% wild-type phosphatase activity or abnormal phenotype pathway to PS3_Supporting).
No variant-specific functional literature: both retrieved full texts (PMID 11237521
17218262) lack any mention of c.387_388del/p.R130Nfs*49.

Sources

cspec ↗vcep_mmc2oncokb ↗PMID:11237521 ↗PMID:17218262 ↗

PS4 PS4 requires either a characteristic phenotype score in affected individuals or variant enrichment in cases versus controls. No proband phenotype data or case-control studies for this variant were available, so this criterion could not be evaluated. Details ▾Hide ▴

Reasoning

The ClinGen PTEN VCEP v3.2 (CSPEC doc 135637575) makes PS4 applicable (default Pathogenic Strong) with two uses: (1) proband phenotype specificity scoring — specificity score >=16 (Very Strong), 4-15.5 (Strong), 2-3.5 (Moderate), 1-1.5 (Supporting); (2) case-control enrichment — prevalence of the variant in affected individuals significantly increased compared with controls (Strong). Neither use can be evaluated from this evidence bundle. The bundle contains no proband phenotype data whatsoever (no proband narratives, no personal/family history, no case-level fields in any source file), so a phenotype specificity score cannot be computed. No case-control or variant-enrichment study of PTEN c.387_388del is present. The variant is absent from ClinVar (search_status=no_result) and unreported in COSMIC, and neither full-text paper available (PMID 11237521, PMID 17218262) mentions the variant or residue R130, so no published case observations exist to derive proband counts. Evidence is insufficient; PS4 is not assessed pending proband phenotype and/or case-control enrichment data.

Rule

ClinGen PTEN VCEP v3.2 PS4 (default Pathogenic Strong): Use 1 - probands with phenotype specificity score >=16 (Very Strong), 4-15.5 (Strong), 2-3.5 (Moderate), 1-1.5 (Supporting); Use 2 - prevalence of the variant in affected individuals significantly increased compared with controls (Strong); detailed scoring thresholds referenced as '(see text)' in the CSPEC

Evidence considered

ClinGen PTEN VCEP v3.2 PS4 rules (structured strength rules): specificity score >=16 (Very Strong)
4-15.5 (Strong)
2-3.5 (Moderate)
1-1.5 (Supporting)
Strong also via prevalence in affected individuals significantly increased vs controls
ClinVar: search_status=no_result
found=false (variant absent from ClinVar)
Evidence bundle scan: no proband
narrative
phenotype
case-level
or family-history content in any bundled source (prefetch.json
evidence.json
literature_pass.json
case_summary.json)
PMID:11237521 and PMID:17218262 full texts searched: variant c.387_388del and residue R130 not mentioned
COSMIC (evidence.json results): no_result
found=false — variant unreported in somatic cancers

Still missing

No proband phenotype data in the case bundle (no narratives/family history in any bundle source) — PTEN VCEP PS4 phenotype specificity score cannot be computed
No case-control or variant-enrichment study of PTEN c.387_388del in affected individuals vs controls — PS4 enrichment use cannot be applied
No published case observations of this exact variant (absent from ClinVar and COSMIC
neither full-text paper mentions it) to derive proband counts for specificity scoring

Sources

PM6 PM6 requires an assumed de novo occurrence (new in the patient without parental confirmation). No de novo observations of any kind were documented for this variant, so this criterion could not be evaluated. Details ▾Hide ▴

Reasoning

Governing framework is the ClinGen PTEN VCEP specification (cspec, v3.2). PM6 requires an assumed de novo occurrence (without confirmation of paternity/maternity) in a proband with the disease and no family history (Moderate), escalating to Strong for two probands with presumed de novo occurrence, and Very Strong for 2 proven / 4 assumed / 1 proven + 2 assumed observations. The case bundle contains no proband-level clinical data: no assumed or proven de novo occurrences are reported, no parental testing was performed or documented, and no family history information is available. ClinVar has no entry for this variant (evidence.json clinvar: search_status no_result), and the only available papers (PMID:11237521, PMID:17218262) are functional-theme and do not mention the variant or any de novo/segregation observations. With zero de novo observations documented, PM6 cannot be applied.

Rule

PTEN VCEP PM6: Moderate = assumed de novo (without confirmation of paternity and maternity) in proband with the disease and no family history; Strong = two probands with presumed de novo occurrence with the disease and no family history; Very Strong = two proven OR four assumed OR one proven + two assumed de novo observations.

Still missing

No presumed/assumed de novo occurrences documented for any proband
No parental testing or family history data captured in the case bundle
No ClinVar or literature observations with inheritance information for c.387_388del

Sources

PP1 PP1 requires evidence that the variant co-segregates with disease in affected family members. No affected relatives were tested and no segregation or pedigree data were available, so this criterion could not be evaluated. Details ▾Hide ▴

Reasoning

Governing framework is the ClinGen PTEN VCEP specification (cspec, v3.2), which defines PP1 by meiosis counts: Supporting = co-segregation with disease in multiple affected family members with 3-4 meioses, Moderate = 5-6 meioses, Strong = >=7 meioses across at least two families. The case bundle contains no segregation data whatsoever: no affected family members tested, no meiosis counts, no co-segregation or non-segregation observations, and no pedigree information. ClinVar has no entry for c.387_388del (evidence.json clinvar: search_status no_result), so no family-based observations are available from submissions. The two available publications (PMID:11237521, PMID:17218262) contain no segregation data and do not mention this variant, so they cannot be used. With zero documented meioses, PP1 cannot be applied.

Rule

PTEN VCEP PP1: Supporting = co-segregation with disease in multiple affected family members with 3 or 4 meioses; Moderate = 5 or 6 meioses; Strong = >=7 meioses across at least two families.

Still missing

No segregation studies or family testing data for c.387_388del (0 meioses documented)
No affected family members genotyped in any family
No ClinVar or literature family-based observations for this variant

Sources

BS3 BS3 requires functional studies showing the variant has no damaging effect. No such studies of this variant were available — the PTEN functional assays cover missense variants only — and all available evidence points to loss of function rather than benign behavior, so this criterion could not be evaluated. Details ▾Hide ▴

Reasoning

No functional evidence of a benign effect exists for this variant. Under the ClinGen PTEN VCEP v3.2, BS3_Supporting requires Mighell et al. 2018 (PMID: 29706350) phosphatase activity >0, which is inapplicable here because the saturation-mutagenesis assay covers missense variants only and c.387_388del is a 2-bp frameshift (no Cum_score lookup possible). BS3_Strong requires well-established studies showing no damaging effect, applied to intronic/synonymous variants via RNA/mini-gene or other splicing assay demonstrating no splicing impact; no such assay data are present, and SpliceAI (max delta 0.01) is an in silico prediction, not a functional assay, and in any case addresses splicing rather than protein function for a truncating variant. No in vitro/in vivo study showing preserved PTEN function for this variant was identified. The indirect evidence in the bundle (catalytic-motif position 123-130, statistically significant hotspot, predicted NMD per PTEN PVS1 decision tree, OncoKB curated LOF label) all point away from a benign functional profile and none constitutes a validated no-damage assay. BS3 is therefore not assessed due to absence of applicable functional data.

Rule

PTEN VCEP v3.2 BS3: Strong = well-established in vitro/in vivo functional studies show no damaging effect on protein function; for intronic or synonymous variants, RNA/mini-gene or other splicing assay demonstrating no splicing impact. Supporting = in vitro/in vivo functional study showing no damaging effect, phosphatase activity >0 per Mighell et al. 2018, PMID: 29706350.

Still missing

No Mighell et al. 2018 (PMID: 29706350) phosphatase activity result applicable: assay is missense-only
variant is a frameshift deletion.
No RNA/mini-gene/splicing assay demonstrating no splicing impact for this variant (BS3_Strong pathway).
No in vitro or in vivo functional study showing no damaging effect on PTEN protein function for c.387_388del.

Sources

cspec ↗vcep_mmc2spliceai ↗oncokb ↗PMID:11237521 ↗PMID:17218262 ↗

BS4 BS4 requires family data showing the variant does not segregate with disease. No segregation or family studies of this variant were available, and absence of segregation data cannot be counted as evidence of lack of segregation, so this criterion could not be evaluated. Details ▾Hide ▴

Reasoning

Governing framework is the ClinGen PTEN VCEP specification (cspec, v3.2): BS4 Supporting = lack of segregation in affected members of one family, Strong = lack of segregation in affected members of two or more families. The case bundle contains no non-segregation evidence: no affected family members tested, no pedigrees showing affected individuals who do not carry the variant, and no segregation analyses of any kind. ClinVar has no entry for NM_000314.8:c.387_388del (evidence.json clinvar: search_status no_result), so there are no submitted family observations demonstrating lack of segregation. The available publications (PMID:11237521, PMID:17218262) are functional-theme and contain no segregation data or variant mention. Absence of segregation data cannot be counted as evidence of lack of segregation; BS4 is therefore not assessed.

Rule

PTEN VCEP BS4: Supporting = lack of segregation in affected members of one family; Strong = lack of segregation in affected members of two or more families.

Still missing

No family segregation analyses performed or reported for this variant
No affected family members tested (cannot demonstrate lack of segregation in any family)
No ClinVar or literature non-segregation observations for c.387_388del

Sources

BP5 BP5 requires documentation that the patient's disease has an alternate molecular cause. No case-level data describing such an alternate cause were available, so this criterion could not be evaluated. Details ▾Hide ▴

Reasoning

The ClinGen PTEN VCEP v3.2 BP5 (Benign Supporting) rule is applicable: '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.' The evidence bundle contains no case-level data at all — no proband narratives, no family history, and no documented alternate molecular basis in any source — so the criterion cannot be evaluated. ClinVar contains no submission for this variant that could document an alternate molecular basis. Evidence is insufficient; BP5 is not assessed pending case-level data.

Rule

ClinGen PTEN VCEP v3.2 BP5 (Benign Supporting): variant found in a case with an alternate molecular basis for disease; other gene/disorder must be 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 rule: variant found in a case with an alternate molecular basis
other gene/disorder must be highly penetrant
personal/family history must show no overlap between other gene and PTEN
ClinVar: search_status=no_result
found=false — no case submissions with an alternate molecular basis reported
Evidence bundle scan: no case-level or family-history content in any bundled source

Still missing

Case-level data required: a case in which the variant is found with an alternate molecular basis (other gene/disorder highly penetrant
and personal/family history showing no PTEN phenotype overlap)
no such case data are present in the evidence bundle

Sources

cspec ↗clinvar ↗

Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 compares a variant's amino-acid change with previously established pathogenic changes. This variant is a frameshift, which has no single alternate amino acid to compare, and it is not a splice-site variant (splice prediction is negligible), so PS1 does not apply. Details ▾Hide ▴

Reasoning

Variant NM_000314.8:c.387_388del is a 2-bp deletion producing a frameshift, NP_000305.3:p.(Arg130AsnfsTer49), not a single amino-acid substitution. The ClinGen PTEN VCEP v3.2 PS1 rule (same amino acid change as a previously established pathogenic variant regardless of nucleotide change, OR a different variant at the same nucleotide position as a pathogenic splicing variant) requires a missense change or splice-site variant for comparison. A frameshift has no single alternate amino acid to compare, and c.387_388del is not a splice-site variant (SpliceAI max delta 0.01). PS1 is therefore inapplicable by variant class; no same-AA comparator was collected (pm5_candidates confirms frameshift is not eligible for classic same-residue searches).

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant (PTEN VCEP v3.2 PS1, Pathogenic Strong).

Evidence considered

ClinGen PTEN VCEP v3.2 PS1 rule (cspec)
pm5_candidates.json: consequence class frameshift
not missense
SpliceAI max delta score 0.01 (no splice impact)

Sources

cspec ↗pm5_candidatesspliceai ↗

PM3 VCEPPM3 applies to recessive disorders, where a variant is found paired with a pathogenic variant on the other copy of the gene. PTEN-related disease is autosomal dominant, and the PTEN expert panel explicitly excludes PM3, so it does not apply. Details ▾Hide ▴

Reasoning

Governing framework is the ClinGen PTEN Expert Panel CSPEC v3.2 (cspec; precedence rank 1, framework_mode vcep), which explicitly declares PM3 'Not Applicable' (applicability field). Generic ACMG PM3 (variant in trans with a pathogenic variant in a recessive disorder) cannot be substituted because PTEN hamartoma tumor syndrome is autosomal dominant (cspec raw_rule_origin: preferredModeOfInheritance 'Autosomal dominant inheritance'; preferredMondoId MONDO:0017623) and the VCEP rule set intentionally omits PM3. PM3 therefore has no applicable rule for this gene/disorder and must not be scored.

VCEP rule

Not applicable per ClinGen PTEN EP CSPEC v3.2 (PM3 applicability declared 'Not Applicable'); PTEN PHTS is autosomal dominant, so the recessive trans-observation basis of PM3 does not apply.

Evidence considered

ClinGen PTEN Expert Panel Specifications v3.2: PM3 applicability = Not Applicable
CSPEC preferredModeOfInheritance = Autosomal dominant inheritance

Sources

PM4 N/APM4 covers in-frame deletions or insertions that change protein length and stop-loss variants. This deletion removes 2 nucleotides (not a multiple of 3), making it a frameshift rather than an in-frame change, so PM4 does not apply; the frameshift effect is already scored under PVS1. Details ▾Hide ▴

Reasoning

PTEN VCEP v3.2 (cspec) PM4 rule: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif (see PM1), and variants causing protein extension.' NM_000314.8:c.387_388del removes 2 nucleotides (not a multiple of 3) and is therefore a frameshift, not an in-frame deletion/insertion, and it is not a stop-loss variant. Frameshift protein-length disruption is captured by PVS1 (met above) and is outside the PM4 scope under both the PTEN VCEP specification and generic ACMG/AMP. PM4 is therefore not applicable to this variant.

Rule

PTEN VCEP v3.2 PM4: in-frame deletions/insertions in a non-repeat region (at least one residue in a catalytic motif per PM1) or stop-loss / protein-extension variants; frameshift variants are out of scope.

Evidence considered

PTEN VCEP v3.2 PM4 rule text limiting PM4 to in-frame deletions/insertions in a non-repeat region (catalytic motif) and stop-loss / protein-extension variants
Variant consequence is frameshift (2-bp deletion
p.Arg130AsnfsTer49)
not in-frame and not stop-loss

Sources

PM5 N/APM5 compares different missense changes at the same amino-acid position. This variant is a frameshift, not a missense change, so there is no alternate amino acid to compare and PM5 does not apply, even though other pathogenic missense changes at residue 130 are known. Details ▾Hide ▴

Reasoning

The PTEN VCEP v3.2 PM5 rule requires a missense change at an amino acid residue where a different missense change has been determined pathogenic/likely pathogenic, plus a BLOSUM62 score comparison. The interrogated variant is a frameshift (p.Arg130AsnfsTer49), not a missense change, so there is no alternate amino acid and no BLOSUM62 comparison to perform. pm5_candidates.json independently concluded the same: eligible_for_classic_pm5_search=false, recommendation level 'not_applicable', reason 'variant consequence class (frameshift) is not missense'. Although alternate pathogenic missense changes at R130 (e.g., R130G/R130Q) are well known in PTEN, PM5 cannot be applied because the variant itself is not a missense change.

Rule

Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant (PTEN VCEP v3.2 PM5, Pathogenic Moderate).

Evidence considered

ClinGen PTEN VCEP v3.2 PM5 rule (missense change required)
pm5_candidates.json: frameshift not eligible for classic same-residue PM5
0 candidates collected

Sources

cspec ↗pm5_candidates

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a frameshift, not a missense change, so PP2 does not apply. Details ▾Hide ▴

Reasoning

The PTEN VCEP v3.2 PP2 rule applies to 'missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The variant is a frameshift (p.Arg130AsnfsTer49), not a missense variant, so PP2 is inapplicable by variant class. Note: PTEN does have missense as a common disease mechanism (the VCEP retains PP2), but this does not rescue PP2 for a non-missense variant.

Rule

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PTEN VCEP v3.2 PP2, Pathogenic Supporting).

Evidence considered

ClinGen PTEN VCEP v3.2 PP2 rule (missense variant required)
Normalized protein consequence p.(Arg130AsnfsTer49) — frameshift
not missense

Sources

PP3 N/APP3's calibrated paths cover splice predictions for synonymous or intronic variants and REVEL scores for missense variants. This is an exonic frameshift, so neither path applies; splice prediction shows no impact on splicing, and applying PP3 would double-count the loss-of-function effect already scored under PVS1. Details ▾Hide ▴

Reasoning

Variant NM_000314.8:c.387_388del is an exonic frameshift (p.(Arg130AsnfsTer49), exon 5) confirmed by Mutalyzer and VariantValidator. The governing specification (ClinGen PTEN EP CSPEC v3.2, doc 135637575) defines only two calibrated PP3 paths: (1) splice-impact concordance of SpliceAI AND VarSeak, scoped by the EP instructions to synonymous or intronic variants, and (2) REVEL score > 0.7 for missense variants. A frameshift indel falls in neither path: REVEL and BayesDel were skipped by the pipeline (non-SNV), and VarSeak is absent from the case bundle. SpliceAI was run and predicts no splice impact (max delta 0.01, DS_AG 0.01), which is directionally against PP3 under any interpretation. No gene-specific PP3/BP4 lookup spreadsheet exists for PTEN (mmc2.xlsx covers PS3/BS3 only; PVS1_DecisionTree_PTEN.pdf covers PVS1 only). Applying PP3 here would also double-count the loss-of-function/null effect that is assessed under PVS1 by the null-variant group (see pvs1_variant_assessment.json downgrade note about not stacking PP3 on null/splice-effect evidence).

Rule

PTEN EP CSPEC v3.2 PP3 (Supporting): 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak; Missense variants: REVEL score > 0.7'. Instructions: apply to synonymous or intronic variants where SpliceAI (0.5-1) and VarSeak (Class 4-5) predict a splicing impact; may also be applied to missense variants with REVEL > 0.7.

Evidence considered

PTEN CSPEC v3.2 PP3 rule (cspec): supporting requires SpliceAI+VarSeak concordance for splicing variants or REVEL > 0.7 for missense
EP instructions scope the splice path to synonymous/intronic variants
SpliceAI lookup (spliceai): max delta score 0.01 (DS_AG 0.01
DS_AL/DS_DG/DS_DL 0.0) - no predicted splice impact
REVEL/BayesDel skipped in prefetch.json/evidence.json with reason 'not snv or no coords'
Variant normalized as frameshift p.(Arg130AsnfsTer49)
exon 5
by Mutalyzer/VariantValidator (prefetch.json)

Still missing

No calibrated computational path applies to frameshift indels: REVEL/BayesDel not computed (non-SNV frameshift)
VarSeak prediction not present in case bundle
EP PP3 splice path requires SpliceAI+VarSeak concordance and would be needed for any splice-impact interpretation of an exonic variant

Sources

PP4 VCEPPP4 is not applicable because the PTEN expert panel has folded phenotype specificity into the PS4 rule and explicitly excludes PP4. Details ▾Hide ▴

Reasoning

The ClinGen PTEN VCEP v3.2 explicitly marks PP4 'Not Applicable' (applicability field in CSPEC doc 135637575): phenotype specificity has been incorporated into the PS4 rule specifications (proband specificity score), so PP4 is not a usable criterion under the governing VCEP framework. Independently, the case bundle contains no proband phenotype data at all, so no phenotype-specificity evidence would exist to support PP4 under any framework. PP4 is not applicable.

VCEP rule

ClinGen PTEN VCEP v3.2 PP4: Not Applicable — phenotype specificity is scored within PS4 (proband specificity score)

Evidence considered

ClinGen PTEN VCEP v3.2 PP4 entry: applicability='Not Applicable'
PTEN EP folds phenotype specificity into PS4 (proband specificity score)

Sources

BP1 VCEPBP1 applies to genes where truncating variants are the only known disease mechanism. Missense variants are a common cause of PTEN disease, so the PTEN expert panel excludes BP1; the variant is also a frameshift, not a missense change. Details ▾Hide ▴

Reasoning

The ClinGen PTEN VCEP v3.2 explicitly marks BP1 as 'Not Applicable' for PTEN: missense variants are a common disease mechanism in PTEN (PTEN hamartoma tumor syndrome), so BP1 (missense variant in a gene for which primarily truncating variants are known to cause disease) cannot be used. Independently, the variant is a frameshift rather than a missense variant, so BP1 is also inapplicable by variant class.

VCEP rule

BP1 (missense variant in a gene for which primarily truncating variants are known to cause disease) — declared Not Applicable by the PTEN VCEP v3.2.

Evidence considered

ClinGen PTEN VCEP v3.2 BP1 applicability: Not Applicable
Normalized protein consequence p.(Arg130AsnfsTer49) — frameshift
not missense

Sources

BP3 VCEPBP3 covers in-frame insertions or deletions in repeat regions without known function. This is a frameshift deletion within the catalytic region, so BP3 does not apply. Details ▾Hide ▴

Reasoning

The PTEN VCEP specification v3.2 (cspec) explicitly marks BP3 as 'Not Applicable' for PTEN, so generic BP3 is superseded. Independently, the generic BP3 criterion (in-frame indels in a repeat region without known function) would not apply: NM_000314.8:c.387_388del is a frameshift deletion in exon 5 within/adjacent to the catalytic P-loop region (codon 130), not an in-frame indel in a repeat region of unknown function. BP3 is therefore not applicable.

VCEP rule

PTEN VCEP v3.2: BP3 Not Applicable. Generic ACMG BP3 (in-frame indels in repeat region without known function) inapplicable to frameshift variants.

Evidence considered

PTEN VCEP v3.2 marks BP3 as Not Applicable
Generic BP3 (in-frame indels in a repeat region without known function) does not apply to a frameshift deletion in a non-repeat catalytic region

Sources

BP4 N/ABP4 requires multiple computational lines of evidence predicting no impact, defined for splice-site and missense variants. This is an exonic frameshift, so the calibrated paths do not apply, and a benign prediction would conflict with the loss-of-function evidence scored under PVS1. Details ▾Hide ▴

Reasoning

The PTEN EP CSPEC v3.2 BP4 rule (Benign Supporting) requires 'multiple lines of computational evidence' of no impact: SpliceAI and VarSeak concordance for splicing variants (scoped by EP instructions to synonymous or intronic variants) or REVEL < 0.5 for missense variants. This variant is an exonic frameshift (p.(Arg130AsnfsTer49)), so the missense path is inapplicable (REVEL/BayesDel skipped as non-SNV) and the EP splice path is out of scope for this variant class. Although SpliceAI (max delta 0.01) falls within the EP benign range (0-0.2), the required VarSeak concordance cannot be established because VarSeak is not present in the case bundle, and a single tool does not constitute 'multiple lines' under the EP rule. Additionally, applying BP4 to a frameshift null variant would conflict with the PVS1-based loss-of-function evidence assessed by the null-variant group.

Rule

PTEN EP CSPEC v3.2 BP4 (Supporting): 'Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak; Missense variants: REVEL scores < 0.5'. Instructions: apply to synonymous or intronic variants where SpliceAI (0-0.2) and VarSeak (Class 1-2) predict no splicing impact.

Evidence considered

PTEN CSPEC v3.2 BP4 rule (cspec): supporting requires SpliceAI+VarSeak concordance (SpliceAI 0-0.2
VarSeak Class 1-2) for splicing variants or REVEL < 0.5 for missense
EP instructions scope to synonymous or intronic variants
SpliceAI lookup (spliceai): max delta score 0.01 - within EP benign range but single tool only
no VarSeak concordance available
VarSeak absent from source_registry/case bundle - concordance requirement of the EP rule cannot be met
Variant class: exonic frameshift p.(Arg130AsnfsTer49) (prefetch.json) - outside BP4 calibrated scope

Still missing

VarSeak prediction not available - EP BP4 splice rule requires concordance of SpliceAI and VarSeak
single-tool SpliceAI 0.01 is insufficient
REVEL/BayesDel not computed - not an SNV (frameshift indel)
missense BP4 path inapplicable

Sources

BP7 N/ABP7 applies to synonymous or intronic variants predicted not to affect splicing. This is a coding (exon 5) frameshift deletion, so BP7 does not apply. Details ▾Hide ▴

Reasoning

PTEN EP CSPEC v3.2 BP7 (Benign Supporting) applies only to 'a synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice' (EP instruction: intronic variants must be at or beyond +7/-21). This variant is a coding (exon 5) frameshift deletion, c.387_388del, p.(Arg130AsnfsTer49) - it is neither synonymous nor intronic. BP7 is therefore definitionally inapplicable; no splice-prediction evaluation is required. The SpliceAI result (max delta 0.01) is noted for completeness but is not used to apply BP7.

Rule

PTEN EP CSPEC v3.2 BP7 (Supporting): 'A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.' Instructions: 'Intronic variants must be positioned at or beyond +7/-21.'

Evidence considered

PTEN CSPEC v3.2 BP7 rule (cspec): applies to synonymous (silent) or intronic variants at or beyond +7/-21 with no predicted splice impact
Variant class confirmed as exonic frameshift p.(Arg130AsnfsTer49) in exon 5 (prefetch.json Mutalyzer/VariantValidator) - not synonymous
not intronic

Still missing

None - criterion is definitionally inapplicable: variant is an exonic frameshift
not synonymous or intronic

Sources

Identifiers

Gene: PTEN
Transcript: NM_000314.8
Coding (HGVS c.): NM_000314.8:c.387_388del
Protein (HGVS p.): NP_000305.3:p.(Arg130AsnfsTer49)
GRCh38: chr10:87933145 GAC>G
GRCh37: chr10:89692902 GAC>G

Gene diagram

Every interpreted variant in PTEN, mapped onto the exon structure of NM_000314.8. Select a row to find it on the plot.

PTENNM_000314.8

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in PTEN — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +350 bp

0.000

SpliceAI acceptor gainat +56 bp

0.010

SpliceAI donor lossat +110 bp

0.000

SpliceAI donor gainat +106 bp

0.000

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Reasoning

Rule

PTEN EP CSPEC v3.2 PP3 (Supporting): 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak; Missense variants: REVEL score > 0.7'. Instructions: apply to synonymous or intronic variants where SpliceAI (0.5-1) and VarSeak (Class 4-5) predict a splicing impact; may also be applied to missense variants with REVEL > 0.7.

Evidence considered

PTEN CSPEC v3.2 PP3 rule (cspec): supporting requires SpliceAI+VarSeak concordance for splicing variants or REVEL > 0.7 for missense
EP instructions scope the splice path to synonymous/intronic variants
SpliceAI lookup (spliceai): max delta score 0.01 (DS_AG 0.01
DS_AL/DS_DG/DS_DL 0.0) - no predicted splice impact
REVEL/BayesDel skipped in prefetch.json/evidence.json with reason 'not snv or no coords'
Variant normalized as frameshift p.(Arg130AsnfsTer49)
exon 5
by Mutalyzer/VariantValidator (prefetch.json)

Still missing

No calibrated computational path applies to frameshift indels: REVEL/BayesDel not computed (non-SNV frameshift)
VarSeak prediction not present in case bundle
EP PP3 splice path requires SpliceAI+VarSeak concordance and would be needed for any splice-impact interpretation of an exonic variant

Sources

Reasoning

Rule

PTEN EP CSPEC v3.2 BP4 (Supporting): 'Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak; Missense variants: REVEL scores < 0.5'. Instructions: apply to synonymous or intronic variants where SpliceAI (0-0.2) and VarSeak (Class 1-2) predict no splicing impact.

Evidence considered

PTEN CSPEC v3.2 BP4 rule (cspec): supporting requires SpliceAI+VarSeak concordance (SpliceAI 0-0.2
VarSeak Class 1-2) for splicing variants or REVEL < 0.5 for missense
EP instructions scope to synonymous or intronic variants
SpliceAI lookup (spliceai): max delta score 0.01 - within EP benign range but single tool only
no VarSeak concordance available
VarSeak absent from source_registry/case bundle - concordance requirement of the EP rule cannot be met
Variant class: exonic frameshift p.(Arg130AsnfsTer49) (prefetch.json) - outside BP4 calibrated scope

Still missing

VarSeak prediction not available - EP BP4 splice rule requires concordance of SpliceAI and VarSeak
single-tool SpliceAI 0.01 is insufficient
REVEL/BayesDel not computed - not an SNV (frameshift indel)
missense BP4 path inapplicable

Sources

BP7 N/ABP7 applies to synonymous or intronic variants predicted not to affect splicing. This is a coding (exon 5) frameshift deletion, so BP7 does not apply. Details ▾Hide ▴

Reasoning

Rule

PTEN EP CSPEC v3.2 BP7 (Supporting): 'A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.' Instructions: 'Intronic variants must be positioned at or beyond +7/-21.'

Evidence considered

PTEN CSPEC v3.2 BP7 rule (cspec): applies to synonymous (silent) or intronic variants at or beyond +7/-21 with no predicted splice impact
Variant class confirmed as exonic frameshift p.(Arg130AsnfsTer49) in exon 5 (prefetch.json Mutalyzer/VariantValidator) - not synonymous
not intronic

Still missing

None - criterion is definitionally inapplicable: variant is an exonic frameshift
not synonymous or intronic

Sources