Variant classification summary

NM_000314.8:c.743del

PTEN · NP_000305.3:p.(Pro248LeufsTer8) · NM_000314.8

GRCh37: chr10:89717716 AC>A · GRCh38: chr10:87957959 AC>A

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PVS1_Very_Strong PM2_Supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Pro248LeufsTer8)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.743del (p.(Pro248LeufsTer8)) variant has been observed in somatic cancers in COSMIC (COSV109436597, n=2) and has been reported in ClinVar as pathogenic.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2_Supporting threshold of 0.001% and supports rarity in the general population.

3

The variant is a frameshift predicted to truncate PTEN at codon 255, and under the PTEN Expert Panel PVS1 decision tree this position is 5' of the p.D375 threshold for full-strength PVS1 in transcript NM_000314.8.

4

SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.06), and this does not alter the interpretation of the variant as a loss-of-function frameshift.

Final determination: Rule20 in the Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as 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	This PTEN frameshift variant, NM_000314.8:c.743del (p.(Pro248LeufsTer8)), is predicted to create a premature termination codon at codon 255, which is well 5' of the PTEN Expert Panel p.D375 (c.1121) threshold for full-strength PVS1 in biologically relevant transcript NM_000314.8. This predicted loss-of-function effect is consistent with an established PTEN disease mechanism and meets PVS1.	cspec pvs1_gene_context pvs1_variant_assessment vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PS1	Not assessed	No evidence was identified that this exact protein consequence has the same amino acid change as a previously established pathogenic variant generated by a different nucleotide change, so PS1 was not assessed.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified, so PS2 was not assessed.	cspec clinvar
PS3	Not assessed	No well-established functional study specific to this variant was identified that would satisfy PTEN PS3. The PTEN saturation mutagenesis phosphatase dataset cited by the Expert Panel applies to missense variants, not this frameshift variant.	cspec vcep_m_m_c_2
PS4	Not assessed	This variant has been reported in ClinVar and has been observed in somatic cancers in COSMIC, but no PTEN hamartoma tumor syndrome proband counts, specificity scores, or case-control enrichment data were identified to meet PTEN PS4.	cspec clinvar PMID:9467011 PMID:15604628 PMID:20301661 PMID:21194675
PM1	Not met	This variant affects codon 248, which is outside the PTEN catalytic motif residues 90-94, 123-130, and 166-168 defined for PM1, and it has not been shown to lie in a qualifying mutational hotspot. Available evidence does not support PM1.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2_Supporting threshold of 0.00001 (0.001%) overall and below the subpopulation threshold of 0.00002 (0.002%). This supports PM2 at supporting strength.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the PTEN Expert Panel specification.	cspec
PM4	N/A	PM4 is reserved for in-frame insertions or deletions and stop-loss variants. This variant is a frameshift, so PM4 is not applicable.	cspec
PM5	N/A	PM5 applies to missense variants at a residue with a different pathogenic missense change. This frameshift variant does not meet that variant type requirement, so PM5 is not applicable.	cspec
PM6	Not assessed	No assumed or confirmed de novo observations were identified for this variant, so PM6 was not assessed.	cspec clinvar
PP1	Not assessed	No segregation data were identified showing this variant co-segregates with PTEN-related disease in affected family members, so PP1 was not assessed.	cspec clinvar
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a frameshift, so PP2 is not applicable.	cspec
PP3	N/A	PTEN PP3 is specified for missense variants with REVEL greater than 0.7 or for splicing variants with concordant splicing predictions. This frameshift variant is not being interpreted as a missense or splice consensus variant, so PP3 is not applicable.	cspec spliceai
PP4	N/A	PP4 is not applicable in the PTEN Expert Panel specification.	cspec
PP5	N/A	PP5 is not applicable in the PTEN Expert Panel specification.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN BA1 threshold of greater than 0.00056 (0.056%). Available evidence does not support BA1.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN BS1 threshold range of 0.000043 to 0.00056 for strong evidence and below 0.0000043 to 0.000043 for supporting evidence. Available evidence does not support BS1.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were identified, so BS2 was not assessed.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing no damaging effect for this variant was identified. The PTEN saturation mutagenesis phosphatase dataset cited for BS3 is indexed for missense variants and does not apply to this frameshift variant.	cspec vcep_m_m_c_2
BS4	Not assessed	No data were identified showing lack of segregation in affected family members, so BS4 was not assessed.	cspec clinvar
BP1	N/A	BP1 is not applicable in the PTEN Expert Panel specification.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/phase unknown with different pathogenic PTEN variants, so BP2 was not assessed.	cspec clinvar
BP3	N/A	BP3 is not applicable in the PTEN Expert Panel specification.	cspec
BP4	N/A	PTEN BP4 is specified for missense variants with REVEL less than 0.5 or for splicing variants with concordant benign splicing predictions. This frameshift variant is not being interpreted as a missense or intronic/synonymous splicing variant, so BP4 is not applicable.	cspec spliceai
BP5	Not assessed	No alternate highly penetrant molecular diagnosis with non-overlapping phenotype was identified, so BP5 was not assessed.	cspec
BP6	N/A	BP6 is not applicable in the PTEN Expert Panel specification.	cspec
BP7	N/A	BP7 applies to synonymous or deep intronic variants with no predicted splicing impact. This variant is a coding frameshift, so BP7 is not applicable.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.