Variant classification summary

NM_000314.8:c.320A>T

PTEN · NP_000305.3:p.(Asp107Val) · NM_000314.8

GRCh37: chr10:89692836 A>T · GRCh38: chr10:87933079 A>T

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3 moderate PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Asp107Val)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PS3 Moderate is supported by the high-confidence D107V phosphatase score of -2.85186154.

2

VUS: PM2 Supporting is supported by absence from the available gnomAD datasets.

3

VUS: PP3 Supporting is supported by a REVEL score of 0.862.

4

VUS: PP5 is recorded as Supporting but is excluded from PTEN VCEP combinations.

Final determination: Under the PTEN VCEP v3.2 framework, PS3 Moderate with PM2 and PP3 Supporting (and no usable PP5 route) satisfies no Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule, so the call is VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: c.320A>T is the missense change p.Asp107Val, whereas the PTEN PVS1 tree covers null, splice-site, deletion, duplication, and initiation-codon variants.	cspec vcep_pvs1_decisiontree_pten
PS1	Not assessed	Not assessed: no established pathogenic alternate-nucleotide variant producing the same p.Asp107Val amino acid change was identified.	cspec clinvar pm5_candidates
PS2	Not assessed	Not assessed: parental testing, confirmed maternity and paternity, and family-history documentation needed to establish a VCEP-defined de novo observation are unavailable.	cspec clinvar
PS3	Met	Met at Moderate: high-confidence D107V phosphatase assay score was -2.85186154, below the VCEP PS3 threshold of ≤ -1.11.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no PTEN specificity score or affected-versus-control counts, odds ratio, confidence interval, or p-value are available for NM_000314.8:c.320A>T.	cspec PMID:23788249 PMID:24493721 PMID:25418537 PMID:25741868 PMID:32350270
PM1	Not met	Not met: p.Asp107Val lies at residue 107, outside the VCEP-defined catalytic-motif intervals 90-94, 123-130, and 166-168.	cspec hotspots
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, below the VCEP’s <0.00001 (0.001%) PM2 frequency threshold.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN Expert Panel explicitly marks PM3 as not applicable to PTEN.	cspec
PM4	N/A	Not applicable: p.Asp107Val is a missense substitution with no protein-length change, stop-loss event, catalytic-motif indel, or protein extension.	cspec
PM5	Not assessed	Not assessed: no pathogenic or likely pathogenic different missense comparator at PTEN residue 107 was available for the required BLOSUM62 comparison.	cspec pm5_candidates
PM6	Not assessed	Not assessed: PMID:25418537 reports PTEN de novo events but does not mention c.320A>T or p.(D107V), and no qualifying variant-specific proband records are available.	cspec clinvar PMID:25418537
PP1	Not assessed	Not assessed: no auditable pedigree documents multiple affected relatives carrying the variant or reports the number of informative meioses.	cspec clinvar
PP2	Not assessed	Not assessed: the required PTEN-specific evidence for both low benign missense variation and a common missense disease mechanism is not available.	cspec
PP3	Met	Met at Supporting: REVEL score 0.862 exceeds the PTEN VCEP missense PP3 threshold of >0.7.	cspec revel
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 instead of allowing independent PP4 application.	cspec
PP5	Met	Not applicable: the PTEN VCEP explicitly prohibits use of PP5 under the ClinGen SVI VCEP Review Committee recommendation.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the >0.00056 (0.056%) BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency falls within either the 0.0000043–0.00056 BS1 range.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygous observation in a healthy or PHTS-unaffected individual is reported, and population records provide absence only.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: high-confidence D107V phosphatase activity was -2.85186154, not greater than the VCEP BS3 threshold of >0.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no family-level data show whether the variant fails to segregate with disease in one or more affected families.	cspec clinvar
BP1	N/A	Not applicable: the PTEN VCEP explicitly marks BP1 as not applicable.	cspec
BP2	Not assessed	Not assessed: no documented trans partner, phase, or three qualifying cis/phase-unknown observations are available for BP2.	cspec clinvar
BP3	N/A	Not applicable: the PTEN VCEP explicitly marks BP3 as Not Applicable, and this variant is a missense substitution rather than a repetitive-region in-frame indel.	cspec
BP4	Not met	Not met: REVEL score 0.862 is above the PTEN VCEP missense BP4 threshold of <0.5.	cspec revel
BP5	Not assessed	Not assessed: no two cases with a highly penetrant alternate molecular diagnosis and non-overlapping PTEN personal or family history are documented.	cspec clinvar
BP6	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of BP6 under the ClinGen SVI VCEP Review Committee recommendation.	cspec
BP7	N/A	Not applicable: the variant is missense, whereas PTEN VCEP BP7 covers only synonymous or intronic variants at or beyond +7/-21.	cspec

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