Variant classification summary

NM_000314.8:c.18A>C

PTEN · NP_000305.3:p.(Lys6Asn) · NM_000314.8

GRCh37: chr10:89624244 A>C · GRCh38: chr10:87864487 A>C

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting PP2 supporting BP4 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Lys6Asn)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

2

PP2 supporting: p.Lys6Asn is a missense variant covered by the PTEN VCEP PP2 specification.

3

BP4 supporting: the REVEL score is 0.489, below the PTEN VCEP cutoff of 0.5.

Final determination: Under the PTEN VCEP Version 3.2 combining rules, the applied PM2, PP2, and BP4 supporting criteria satisfy neither a pathogenic rule nor a benign rule, so the variant is classified as 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.18A>C is a missense substitution, whereas the PTEN PVS1 decision tree covers specified loss-of-function consequence classes.	cspec vcep_pvs1_decisiontree_pten
PS1	Not assessed	Not assessed: no verified previously established pathogenic variant with the same p.Lys6Asn amino-acid change was available, and comparator retrieval had a documented soft failure.	cspec clinvar pm5_candidates
PS2	Not assessed	Not assessed: no proband-level de novo observation, parental testing, maternity/paternity confirmation, or family-history information is available.	cspec
PS3	Not met	Not met: high-confidence K6N Cum_score was -1.045273268, above the PTEN VCEP PS3_Moderate cutoff of <= -1.11.	vcep_mmc2 PMID:29706350 PMID:27147599
PS4	Not assessed	Not assessed: no case-control statistics or phenotype-specificity score are available to compare with the VCEP's PS4 requirements.	cspec
PM1	Not met	Not met: p.Lys6Asn is at residue 6, outside VCEP catalytic motifs 90-94, 123-130, and 166-168, with no statistically significant hotspot reported.	cspec
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN VCEP PM2 threshold of <0.00001 (0.001%).	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly marks PM3 “Not Applicable.”	cspec
PM4	N/A	Not applicable: p.(Lys6Asn) is a missense substitution with no protein-length change, not an in-frame indel or stop-loss variant.	cspec
PM5	Not assessed	Not assessed: no qualifying pathogenic or likely pathogenic alternate missense at Lys6 was verified, and the required BLOSUM62 comparison is unavailable.	cspec pm5_candidates
PM6	Not assessed	Not assessed: zero documented presumed or assumed de novo observations and no disease or family-history data are available.	cspec
PP1	Not assessed	Not assessed: no affected relatives, co-segregation observations, or meiosis count are documented for this variant.	cspec
PP2	Met	Met at supporting strength: p.Lys6Asn is a missense variant, and the PTEN VCEP specifies PP2 for PTEN's low benign-missense rate and common missense disease mechanism.	cspec
PP3	Not met	Not met: the missense REVEL score is 0.489, below the PTEN VCEP PP3 threshold of greater than 0.7.	cspec revel
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 rather than allowing independent PP4 use.	cspec
PP5	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of PP5 under its specification.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the BA1 threshold of >0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: no gnomAD allele frequency was observed, so the variant does not fall within either BS1 interval from 0.0000043 to 0.00056.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 report zero observed alleles, providing no homozygous healthy-individual observation required for BS2.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: high-confidence K6N Cum_score was -1.045273268, not greater than the PTEN VCEP BS3_Supporting threshold of >0.	vcep_mmc2 PMID:29706350 PMID:27147599
BS4	Not assessed	Not assessed: no affected-family testing or lack-of-segregation observation is documented in one or more families.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no cis/trans or phase information links this variant to a different pathogenic or likely pathogenic PTEN variant.	cspec clinvar
BP3	N/A	Not applicable: the PTEN VCEP explicitly marks BP3 as Not Applicable, and this variant is a missense substitution.	cspec
BP4	Met	Met: the missense REVEL score is 0.489, below the PTEN VCEP BP4 threshold of less than 0.5.	cspec revel
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate disorder and non-overlapping PTEN history are documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of BP6 under its specification.	cspec
BP7	N/A	Not applicable: c.18A>C is an exonic missense variant, whereas PTEN VCEP BP7 covers only synonymous or intronic variants at or beyond +7/-21.	cspec

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