NM_000314.8:c.634+1G>C

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89712017 G>C · GRCh38: chr10:87952260 G>C

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PVS1 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

The PTEN c.634+1G>C (p.?) variant has been observed in somatic cancers in COSMIC (COSV64295775; 2 occurrences) and has been reported in ClinVar as pathogenic by three clinical laboratories.

This variant is absent from gnomAD v2.1 and gnomAD v4.1.

In silico splicing analysis predicts a marked effect on RNA processing, with a SpliceAI maximum delta score of 0.99, consistent with disruption of the canonical donor site.

Final determination: Likely pathogenic based on 1 Very Strong pathogenic criterion (PVS1) and 1 Supporting pathogenic criterion (PM2_Supporting), satisfying the framework rule for Likely Pathogenic.

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	NM_000314.8:c.634+1G>C disrupts the canonical +1 donor site of intron 6 in the biologically relevant transcript NM_000314.8. The PTEN-specific PVS1 decision tree indicates that canonical GT-AG splice-site disruption at or 5' to c.1121 (p.D375) is assigned PVS1; this variant is upstream of that threshold and is therefore consistent with PTEN loss of function under the PTEN VCEP rule.	cspec vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PS1	Not assessed	PTEN permits PS1 for a different variant at the same nucleotide position as a known pathogenic splicing variant if in silico impact is equal to or greater than the known pathogenic variant, but no same-position comparator variant with the necessary side-by-side evidence was documented.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was documented.	cspec clinvar
PS3	Not assessed	PTEN allows PS3 for RNA, minigene, or other assays showing splicing impact, but no directly extracted assay result for NM_000314.8:c.634+1G>C was documented here. The local PTEN functional spreadsheet is a missense phosphatase assay resource and is not applicable to this splice donor variant.	cspec vcep_m_m_c_2 PMID:28677221
PS4	Not assessed	The variant is present in ClinVar and reported in COSMIC, but no proband specificity scoring, case-count synthesis, or case-control analysis meeting PTEN PS4 thresholds was documented.	cspec clinvar cosmic
PM1	N/A	PM1 is specified for residues within PTEN catalytic motifs and mutational hotspot/domain contexts. This variant is a canonical splice donor variant rather than a coding residue change within the defined catalytic motifs.	cspec
PM2	Met	The variant is absent from both gnomAD v2.1 and gnomAD v4.1, satisfying the PTEN PM2_Supporting population rarity rule.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not for use in this PTEN VCEP specification.	cspec
PM4	N/A	PM4 is specified for in-frame insertions/deletions or stop-loss variants causing protein length change and does not fit a canonical splice donor substitution.	cspec
PM5	N/A	PM5 is a missense residue-based rule and does not apply to this canonical splice donor variant.	cspec
PM6	Not assessed	No presumed de novo occurrences in affected individuals without family history were documented.	cspec clinvar
PP1	Not assessed	No segregation data with informative meioses were documented.	cspec
PP2	N/A	PP2 is a missense-specific rule and does not apply to a canonical splice donor variant.	cspec
PP3	Not assessed	SpliceAI predicts a strong splice effect with a maximum delta score of 0.99, but the PTEN PP3 rule for splicing variants requires concordance of SpliceAI and VarSeak. VarSeak output was not documented, so PP3 was not applied in this pass.	cspec spliceai
PP4	N/A	PP4 is designated not applicable by the PTEN VCEP because phenotype specificity is incorporated into PS4 specifications.	cspec
PP5	N/A	PP5 is not for use in this PTEN VCEP specification.	cspec
BA1	Not met	The variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the PTEN BA1 frequency threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet PTEN BS1 or BS1_Supporting allele-frequency thresholds.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were documented.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	No RNA, minigene, or other functional study demonstrating no splicing impact for this canonical splice donor variant was documented.	cspec vcep_m_m_c_2
BS4	Not assessed	No nonsegregation data in one or more families were documented.	cspec
BP1	N/A	BP1 is designated not applicable by the PTEN VCEP.	cspec
BP2	Not assessed	No phase data with other pathogenic or likely pathogenic PTEN variants were documented.	cspec
BP3	N/A	BP3 is designated not applicable by the PTEN VCEP.	cspec
BP4	Not met	Benign computational evidence was not observed. SpliceAI predicts a strong splice effect with a maximum delta score of 0.99, which argues against BP4.	cspec spliceai
BP5	Not assessed	No evidence was documented showing that affected individuals carrying this variant had an alternate highly penetrant molecular diagnosis with nonoverlapping phenotype.	cspec
BP6	N/A	BP6 is not for use in this PTEN VCEP specification.	cspec
BP7	N/A	BP7 is specified for synonymous variants or intronic variants at or beyond +7/-21 with no predicted splice effect. This variant is a canonical +1 splice donor substitution, so BP7 does not apply.	cspec spliceai

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