Variant classification summary

NM_000314.8:c.1027-1G>C

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89725043 G>C · GRCh38: chr10:87965286 G>C

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PVS1_Strong PS1_Strong PM2_Supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN-specific PVS1 decision tree supports PVS1_Strong for this canonical splice acceptor variant because it affects the exon 9 acceptor of NM_000314.8, and preserved-frame loss of entire exon 9 is explicitly treated as a critical altered region in PTEN.

2

PS1_Strong is met because ClinVar contains a same-nucleotide pathogenic splicing variant at NM_000314.8:c.1027-1G>A.

3

The queried variant shows equal predicted splice acceptor loss to the known pathogenic same-position variant by SpliceAI (DS_AL 0.99), satisfying the PTEN same-position splicing use of PS1.

4

PM2_Supporting is met because the variant is absent from both gnomAD v2.1 and gnomAD v4.1.

5

No assembled RNA assay, de novo series, segregation dataset, or PTEN PS4 phenotype-scored case series was available to upgrade beyond the current evidence combination.

Final determination:

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	Met	PTEN-specific PVS1 guidance supports PVS1_Strong for this canonical splice acceptor variant at NM_000314.8:c.1027-1G>C. The affected site is the acceptor of exon 9; exon 9 loss preserves reading frame, and the PTEN decision tree explicitly treats entire exon 9 as a critical altered region for GT-AG splice-site variants.	vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n cspec
PS1	Met	PTEN PS1_Strong is met because a different substitution at the same nucleotide position is already established as pathogenic in ClinVar (NM_000314.8:c.1027-1G>A), and SpliceAI predicts equal splice acceptor loss for the queried variant and the known pathogenic same-position variant (DS_AL 0.99 for both).	clinvar spliceai cspec
PS2	Not assessed	No confirmed de novo evidence was assembled in the reviewed workspace.	cspec
PS3	Not assessed	No PTEN RNA, minigene, or other splicing assay demonstrating abnormal splicing for this variant was assembled. The PTEN mmc2 functional file is missense-specific and not applicable to this splice variant.	cspec vcep_m_m_c_2
PS4	Not assessed	The workspace did not provide PTEN-scored proband phenotype specificity data or a qualifying case-control dataset to calculate PS4.	cspec clinvar
PM1	N/A	PM1 in PTEN is defined for missense changes in catalytic motifs at residues 90-94, 123-130, and 166-168; this is a splice acceptor variant outside that missense/domain use case.	cspec
PM2	Met	PM2_Supporting is met because the variant is absent from both gnomAD v2.1 and gnomAD v4.1, satisfying the PTEN EP ultra-rare population threshold.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in the PTEN VCEP framework.	cspec
PM4	N/A	PM4 is reserved for in-frame indels or stop-loss variants, not for this canonical splice acceptor SNV.	cspec
PM5	N/A	PM5 is a missense-specific rule and does not apply to this splice acceptor variant.	cspec
PM6	Not assessed	No assumed de novo evidence was assembled in the workspace.	cspec
PP1	Not assessed	No segregation data were assembled.	cspec
PP2	N/A	PP2 is a missense-context rule and does not apply to this splice acceptor variant.	cspec
PP3	Not assessed	SpliceAI strongly predicts splice impact (max delta 0.99), but the PTEN EP splicing PP3 rule requires concordance of SpliceAI and VarSeak. VarSeak evidence was not assembled in this workspace, so PP3 was not applied.	spliceai cspec
PP4	N/A	PP4 is not applicable in the PTEN VCEP framework because phenotype specificity is incorporated into PS4 specifications.	cspec
PP5	N/A	PP5 is not for use in this PTEN VCEP framework.	cspec
BA1	Not met	BA1 is not met because the variant is absent from gnomAD.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	BS1 is not met because the variant is absent from gnomAD rather than exceeding PTEN benign frequency thresholds.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No homozygous observations in healthy or PTEN-unaffected individuals were assembled.	cspec
BS3	Not assessed	No RNA or other splicing assay demonstrating no impact on splicing was assembled.	cspec vcep_m_m_c_2
BS4	Not assessed	No lack-of-segregation evidence was assembled.	cspec
BP1	N/A	BP1 is not applicable to PTEN in this VCEP framework.	cspec
BP2	Not assessed	No phase data with other pathogenic/likely pathogenic PTEN variants were assembled.	cspec
BP3	N/A	BP3 is not applicable to PTEN in this VCEP framework.	cspec
BP4	Not met	BP4 is not met because SpliceAI predicts strong splice impact (max delta 0.99), and PTEN BP4 for splicing additionally requires benign no-impact concordance of SpliceAI and VarSeak.	spliceai cspec
BP5	Not assessed	The workspace did not document at least two cases with an alternate highly penetrant diagnosis and non-overlapping PTEN phenotype.	cspec
BP6	N/A	BP6 is not for use in this PTEN VCEP framework.	cspec
BP7	N/A	BP7 applies only to synonymous variants or intronic variants at or beyond +7/-21 with no splice impact; this variant is a canonical -1 splice acceptor change.	cspec spliceai

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