PTEN c.320A>T, p.Asp107Val

Reasoning

The PTEN VCEP permits PS3 at Moderate strength for well-established functional studies showing damaging effect when phosphatase activity is ≤ -1.11 per Mighell et al. 2018. In Table S2 of mmc2.xlsx, the exact missense variant D107V/Asp107Val is listed with Cum_score -2.85186154 and High_conf=True (Pass SE Filter), which satisfies the VCEP's high-confidence requirement and the ≤ -1.11 threshold. The variant is therefore PS3_Moderate.

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 Version 3.2 PS3_Moderate rule: phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350; Table S2 requires the variant to be listed as TRUE under High_conf.
• Mighell et al. 2018 supplementary mmc2.xlsx, Table S2, row D107V / Asp107Val: Cum_score=-2.85186154, High_conf=True, High_conf_nature=Pass SE Filter, Imputed_Score=NA, Type=missense.
• The exact variant is also represented in the file's ClinVar table as NM_000314.6(PTEN):c.320A>T (p.Asp107Val), confirming the searched variant identity.

Sources

Reasoning

The PTEN VCEP permits PM2 at Supporting strength when a variant is present at an allele frequency below 0.00001 (0.001%) in gnomAD or another large sequenced population; if multiple alleles occur in a subpopulation, that subpopulation frequency must be below 0.00002 (0.002%). The variant is absent from gnomAD v2.1 and v4.1, and also absent from the available non-cancer subsets, satisfying the stated frequency 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 Supporting applies to variants absent in population databases or 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 frequency must be <0.00002 (0.002%).
• GNOMAD_V2_1: absent from gnomAD v2.1; source_data is empty and no allele frequency is reported.
• GNOMAD_V4_1: absent from gnomAD v4.1; source_data is empty and no allele frequency is reported.
• GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER also report the variant as absent.

Sources

Reasoning

The variant is missense (NM_000314.8:c.320A>T, p.(Asp107Val)). The PTEN VCEP PP3 missense rule names REVEL and requires a score > 0.7; the available REVEL score is 0.862, which meets the threshold. SpliceAI is not used for this PP3 decision because the VCEP names it for splicing variants, not the missense path.

VCEP rule

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

Evidence considered

• PTEN VCEP PP3 missense rule: REVEL score > 0.7.
• Local REVEL predictor lookup for PTEN c.320A>T (p.Asp107Val): score 0.862.

Sources

Reasoning

Expert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Pathogenic.

VCEP rule

This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

Evidence considered

• ClinGen PTEN Expert Panel Specification v3.2, PP5 entry: applicability is "Not Applicable for this VCEP" and the instructions state, "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee."
• ClinVar expert panel classification

Sources

Reasoning

The PTEN VCEP defines PM1 to include residues in catalytic motifs 90-94, 123-130, and 166-168 of NP_000305.3. The variant is p.Asp107Val, outside all three specified regions. Although the evidence reports a D107 cancer hotspot, the VCEP does not name a hotspot source or provide a separate hotspot route, so that observation does not satisfy this rule.

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

• The governing PTEN VCEP PM1 rule defines the critical regions as residues 90-94, 123-130, and 166-168 (NP_000305.3).
• The variant is NP_000305.3:p.(Asp107Val), so residue 107 is outside every VCEP-defined catalytic-motif interval.
• Cancer Hotspots reports a statistically significant PTEN D107 hotspot, but the PTEN VCEP rule does not name Cancer Hotspots, COSMIC, or another hotspot route as an independent PM1 path.

Sources

Reasoning

The PTEN VCEP defines BA1 as a filtering allele frequency greater than 0.00056 (0.056%) in gnomAD. The variant is absent from gnomAD v2.1 and gnomAD v4.1, with no filtering allele frequency meeting or exceeding the BA1 threshold. The available non-cancer subsets also report the variant as absent.

VCEP rule

gnomAD Filtering allele frequency >0.00056 (0.056%)

Evidence considered

• ClinGen PTEN VCEP Version 3.2: BA1 rule is gnomAD filtering allele frequency >0.00056 (0.056%).
• GNOMAD_V2_1: absent from gnomAD v2.1; source_data is empty and no allele frequency is reported.
• GNOMAD_V4_1: absent from gnomAD v4.1; source_data is empty and no allele frequency is reported.
• GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER also report the variant as absent; no alternate population-source frequency is available.

Sources

Reasoning

The PTEN VCEP defines BS1 Strong as a gnomAD filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%), and BS1 Supporting as 0.0000043 (0.00043%) up to 0.000043 (0.0043%). The variant is absent from gnomAD v2.1 and v4.1 and therefore does not meet either frequency interval. The available non-cancer subsets also report absence.

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 requires gnomAD filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).
• ClinGen PTEN VCEP Version 3.2: BS1 Supporting requires allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).
• GNOMAD_V2_1: absent from gnomAD v2.1; source_data is empty and no allele frequency is reported.
• GNOMAD_V4_1: absent from gnomAD v4.1; source_data is empty and no allele frequency is reported.
• GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER also report the variant as absent.

Sources

Reasoning

The PTEN VCEP permits BS3 at Supporting strength for functional studies showing no damaging effect when phosphatase activity is >0 per Mighell et al. 2018. The exact high-confidence D107V/Asp107Val entry in Table S2 has Cum_score -2.85186154, not >0, and instead supports damaging functional effect; no qualifying variant-specific benign assay result is available. BS3 is therefore not met.

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 Version 3.2 BS3_Supporting rule: phosphatase activity >0 per Mighell et al. 2018, PMID: 29706350.
• Mighell et al. 2018 supplementary mmc2.xlsx, Table S2, row D107V / Asp107Val: Cum_score=-2.85186154 and High_conf=True (Pass SE Filter); the score is below, rather than above, zero.
• The exact variant is also represented in the file's ClinVar table as NM_000314.6(PTEN):c.320A>T (p.Asp107Val), confirming the searched variant identity.

Sources

Reasoning

The variant is missense, so the PTEN VCEP BP4 missense path applies and requires REVEL < 0.5. The available REVEL score is 0.862, which does not meet that benign threshold. SpliceAI is not used for this BP4 decision because the VCEP names it for splicing variants, not the missense path.

VCEP rule

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

Evidence considered

• PTEN VCEP BP4 missense rule: REVEL scores < 0.5.
• Local REVEL predictor lookup for PTEN c.320A>T (p.Asp107Val): score 0.862, above the BP4 cutoff.

Sources

Reasoning

The PTEN VCEP requires the same amino acid change as a previously established pathogenic variant, regardless of nucleotide change, for PS1. The available evidence establishes this variant as p.Asp107Val, but does not identify a different nucleotide change producing the same amino acid change with an established pathogenic classification.

VCEP 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.

Evidence considered

• The case variant is NM_000314.8:c.320A>T, NP_000305.3:p.(Asp107Val).
• ClinVar records NM_000314.8:c.320A>T (p.Asp107Val) as Pathogenic, but this is the queried variant itself and does not demonstrate a different nucleotide change with the same amino acid consequence.
• The same-residue comparator search reported zero useful candidates; it did not establish a qualifying alternate-nucleotide p.Asp107Val variant.

Still missing

• A verified alternate-nucleotide PTEN variant producing p.Asp107Val with an established pathogenic classification is needed.

Sources

Reasoning

The available case evidence does not document a proband-level de novo observation for NM_000314.8:c.320A>T, confirmation of both maternity and paternity, or absence of family history. ClinVar metadata lists one submission origin as maternal, but this does not establish the VCEP PS2 requirement or provide the necessary parental-testing details. The criterion therefore cannot be evaluated without primary pedigree and parental-genotyping records.

VCEP rule

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

Evidence considered

• ClinVar exact variant record NM_000314.8(PTEN):c.320A>T (p.Asp107Val), Variation ID 372481, contains a submission with origin listed as maternal but does not provide proband-level parental testing or family-history documentation.
• No case-level record in the available evidence establishes both maternity and paternity or proves de novo occurrence for this variant.

Still missing

• Proband-level documentation of the variant and phenotype
• Parental genotyping confirming maternity and paternity
• Documented absence of family history

Sources

Reasoning

The PTEN VCEP permits PS4 from phenotype-specificity scores or from a case-control comparison in which variant prevalence is significantly increased in affected individuals compared with controls. The available case contains no Cleveland Clinic score, pediatric phenotype score, proband count meeting the PTEN rubric, affected/control genotype counts, odds ratio, confidence interval, or p-value. The literature packet's ai_classified_papers array is empty; the available extracted candidate papers were checked and do not report this exact variant with qualifying phenotype-specificity or case-control data: PMID:23788249, PMID:24493721, PMID:25418537, PMID:25741868, and PMID:32350270. The variant's absence from gnomAD is population evidence but does not by itself establish the VCEP's required affected-versus-control comparison or a PTEN specificity score.

VCEP rule

Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.

Evidence considered

• ClinGen PTEN Expert Panel Specification v3.2, PS4: the case-control path permits application when a sufficiently powered study finds an odds ratio >2 for a PHTS component phenotype with p<0.05 and a 95% confidence-interval lower limit >1.5; the specificity-score path assigns 1 point per adult proband with Cleveland Clinic score >=30, 0.5 points for 25-29, 1 point per child with pediatric phenotype score >=5, and 0.5 points for score 4 with autism/developmental delay/intellectual disability excluded.
• ClinGen PTEN Expert Panel Specification v3.2, PS4 strength rules: PS4_Very Strong requires specificity score >=16; PS4 Strong requires specificity score 4-15.5 or significantly increased variant prevalence in affected individuals compared with controls; PS4_Moderate requires score 2-3.5; PS4_Supporting requires phenotype specificity with score 1-1.5.
• The case materials provide no Cleveland Clinic score, pediatric phenotype score, independent-proband specificity total, affected/control genotype counts, odds ratio, confidence interval, or p-value for NM_000314.8:c.320A>T.
• Literature review: literature_pass.json reports ai_classified_papers as an empty array. PMID:23788249, PMID:24493721, PMID:25418537, PMID:25741868, and PMID:32350270 were checked through paper_extracts.json; none reports this exact PTEN variant with qualifying PS4 case-control or phenotype-specificity evidence.
• GNOMAD_V2_1 and GNOMAD_V4_1 report the variant as absent, but those records contain no affected-case comparison and cannot substitute for the PS4 evidence paths.

Still missing

• Cleveland Clinic score or qualifying pediatric phenotype score for each independent proband, or a sufficiently powered case-control dataset with affected/control counts or an odds ratio, confidence interval, and p-value.

Sources

Reasoning

The PTEN VCEP requires a different missense change at the same amino acid residue that is pathogenic or likely pathogenic, plus a BLOSUM62 score for the interrogated variant equal to or less than that of the known variant. No same-residue comparator was identified, so the required comparator classification and score comparison cannot be evaluated.

VCEP 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.

Evidence considered

• The variant is NP_000305.3:p.(Asp107Val), at residue 107.
• The PM5 candidate artifact reported 10 candidates reviewed but zero same-residue candidates, with zero expert-panel or non-expert-majority pathogenic/likely pathogenic same-residue candidates.
• Because no qualifying different missense comparator was identified, the VCEP's required BLOSUM62 comparison cannot be completed.

Still missing

• A verified pathogenic or likely pathogenic PTEN missense variant at residue 107 and its BLOSUM62 score are needed.

Sources

Reasoning

The available evidence does not establish an assumed de novo observation of NM_000314.8:c.320A>T in a patient with disease and no family history, nor does it provide multiple qualifying probands. PMID:25418537 reports de novo PTEN events in simplex autism cohorts but does not mention c.320A>T or p.(D107V), so it cannot supply a variant-specific PM6 observation. The criterion remains not assessed pending primary case reports with phenotype, family-history, and parental-testing details.

VCEP rule

Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history. ... Two probands with presumed _de novo_ occurrence (maternity/ paternity not confirmed) with the disease and no family history. ... Assumed _de novo,_ but without confirmation of paternity and maternity, in proband with the disease and no family history.

Evidence considered

• ClinVar exact variant record cites PMIDs including PMID:25418537 but does not itself provide the required variant-specific de novo proband details.
• PMID:25418537, Results/Table 1, reports PTEN de novo events in simplex autism cohorts but explicitly does not mention PTEN c.320A>T or p.(D107V); it therefore does not document a qualifying observation for this variant.

Still missing

• Variant-specific proband observations with disease
• Documented absence of family history for each proband
• Parental-testing status for each presumed de novo observation

Sources

Reasoning

The available evidence does not provide a pedigree showing NM_000314.8:c.320A>T co-segregating with disease in multiple affected family members, and no count of informative meioses is documented. A ClinVar submission origin labeled maternal and a submission-level statement about segregation are insufficient without the underlying family members, genotypes, phenotypes, and meiosis count. PP1 therefore cannot be assessed.

VCEP rule

Co-segregation with disease in multiple affected family members, with ≥7 meioses observed across at least two families. ... Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. ... Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.

Evidence considered

• ClinVar exact variant record does not provide an auditable pedigree, tested relatives, variant genotypes, phenotype status, or informative meiosis count.
• No primary family-level segregation data for this variant are available in the reviewed case evidence.

Still missing

• Pedigree with affected relatives and variant genotypes
• Phenotype status for each tested family member
• Informative meiosis count

Sources

Reasoning

The PTEN VCEP PP2 rule requires both a low rate of benign missense variation and missense variants being a common disease mechanism. The available evidence confirms a missense variant and PTEN loss-of-function context, but does not provide VCEP-governed evidence establishing both PP2 conditions.

VCEP 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.

Evidence considered

• The variant is a missense change, p.Asp107Val.
• The PTEN VCEP PP2 rule requires the gene-level properties of low benign missense variation and a common missense disease mechanism; the available case evidence does not document both properties under this VCEP rule.

Still missing

• VCEP-governed evidence establishing PTEN's low rate of benign missense variation and common missense disease mechanism is needed.

Sources

Reasoning

The PTEN VCEP requires observation of the variant in the homozygous state in a healthy or PHTS-unaffected individual, with one confirmed observation or two observations when parental confirmation is unavailable. The available population records report absence only and provide no homozygote observations or clinical status, so BS2 cannot be assessed.

Evidence considered

• ClinGen PTEN VCEP Version 3.2: BS2 requires the variant to be observed in the homozygous state in a healthy or PHTS-unaffected individual; one observation is sufficient if homozygous status is confirmed and two are required if it is not confirmed.
• GNOMAD_V2_1 and GNOMAD_V4_1 report the variant as absent and provide no homozygote count or clinical-status information.
• GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER also report absence without homozygote or clinical-status data.

Still missing

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

Sources

Reasoning

The available evidence does not document lack of segregation of NM_000314.8:c.320A>T in affected family members from either one family or two or more families. No affected relatives, variant-negative affected individuals, or family-level phenotype/genotype data are provided. BS4 therefore cannot be evaluated.

VCEP rule

Lack of segregation in affected members of two or more families. ... Lack of segregation in affected members of one family.

Evidence considered

• ClinVar exact variant record does not provide affected-relative testing results or family-level non-segregation data.
• No primary pedigree evidence documenting lack of segregation in one or more families is available.

Still missing

• Affected family members tested for the variant
• Variant and phenotype results for each affected relative
• Number of families with informative non-segregation

Sources

Reasoning

BP2 is applicable 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 and/or phase unknown with different pathogenic or likely pathogenic PTEN variants. The available ClinVar record identifies this variant as maternal in one submission but does not document a second pathogenic or likely pathogenic PTEN variant, its phase, or three qualifying cis/phase-unknown observations. The BP2 rule therefore cannot be evaluated from the available evidence.

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 entry: the Supporting rule requires observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants.
• ClinVar Variation 372481, NM_000314.8(PTEN):c.320A>T (p.Asp107Val): one submission records maternal origin, but the record provides no documented second PTEN variant, phase relationship, or three qualifying cis/phase-unknown observations.

Still missing

• Documented observation with a pathogenic or likely pathogenic PTEN variant in trans, or at least three observations with different pathogenic or likely pathogenic PTEN variants in cis or phase unknown.

Sources

Reasoning

The PTEN VCEP requires a variant to be found in a case with an alternate molecular basis for disease; the alternate gene/disorder must be highly penetrant, the patient's personal/family history must show no overlap with PTEN, and the VCEP instructions require at least two such cases. The available evidence documents PTEN pathogenicity and general disease associations but does not provide at least two qualifying cases with a highly penetrant alternate molecular diagnosis and non-overlapping personal/family history. BP5 therefore cannot be evaluated.

VCEP rule

At least two such cases are required for criteria to apply. ... 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

• ClinGen PTEN Expert Panel Specification v3.2, BP5 instructions: "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."
• ClinGen PTEN Expert Panel Specification v3.2, BP5 Supporting 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."
• ClinVar Variation 372481 identifies the exact variant as pathogenic but provides no two qualifying alternate-molecular-basis cases, highly penetrant alternate diagnosis, or non-overlapping personal/family history.

Still missing

• At least two documented cases carrying NM_000314.8:c.320A>T with a highly penetrant alternate gene/disorder and personal/family histories demonstrating no overlap with PTEN.

Sources