Variant classification summary

NM_000314.8:c.143A>C

PTEN · NP_000305.3:p.(Asn48Thr) · NM_000314.8

GRCh37: chr10:89653845 A>C · GRCh38: chr10:87894088 A>C

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3 moderate PM2 supporting PP2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Asn48Thr)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.143A>C p.(Asn48Thr) is a missense variant in PTEN exon 2.

2

This variant is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).

3

Mighell et al. 2018 PTEN saturation mutagenesis functional assay demonstrates a damaging effect with a cumulative fitness score of -3.41 (<= -1.11 threshold, High_conf = True), qualifying for PS3_Moderate per the PTEN VCEP v3.2.0.

4

REVEL score of 0.919 exceeds the VCEP PP3 threshold of >0.7 for missense variants.

5

PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PHTS (PP2).

6

Residue N48 lies outside the VCEP-defined catalytic motifs (90-94, 123-130, 166-168); PM1 is not met.

7

No de novo observations, segregation data, proband counting data, or alternate molecular basis cases were available for this variant.

8

ClinVar reports this variant as Uncertain significance (2 clinical laboratories, variationID 373667).

9

Summary of met criteria: PS3_Moderate + PM2_Supporting + PP2 + PP3. Per the PTEN VCEP final classification framework, this combination does not reach the Likely Pathogenic threshold (Rule11 requires PVS1_Strong/PS1/PS2/PS3/PS4/PM6_Strong/PP1_Strong >=1 AND PVS1_Moderate/PS3_Moderate/PS4_Moderate/PM1/PM4/PM5/PM6/PP1_Moderate ==1; Rule13 requires >=3 Moderate criteria). With 1 Moderate (PS3_Moderate) and 3 Supporting (PM2_Supporting, PP2, PP3), the variant remains classified as Uncertain significance.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v3.2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	Missense variant p.(Asn48Thr); the PTEN VCEP PVS1 decision tree applies only to null variants (nonsense, frameshift, canonical GT-AG splice disruptions, CNV). This variant does not fall into any PVS1-eligible bucket.	cspec pvs1_generic_framework
PS1	Not assessed	No previously established pathogenic variant with the same amino acid change (p.Asn48Thr) was identified. No other variant at c.143 with a pathogenic splicing effect was identified.	cspec
PS2	Not assessed	No de novo observations (confirmed or assumed) were identified for this variant in the available evidence.
PS3	Met	Mighell et al. 2018 (PMID: 29706350) massively parallel phosphatase activity assay: N48T cumulative fitness score = -3.41, which is <= the VCEP PS3_Moderate threshold of -1.11 (High_conf = True, Pass SE Filter).	vcep_mmc2
PS4	Not assessed	No proband counting data with PTEN specificity scores was available for this variant. ClinVar reports only 2 clinical laboratory submissions as VUS with no criterion-lead submissions usable for proband enumeration.	clinvar
PS5	N/A	PS5 is not defined in the PTEN VCEP v3.2.0 framework criteria set; replaced by PS2/PM6 hierarchy in contemporary ACMG/AMP application.	cspec
PM1	Not met	Residue N48 is outside the PTEN VCEP-defined catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168; NP_000305.3). Although a statistically significant hotspot was detected, the VCEP PM1 rule is restricted to residues within the specified catalytic motifs.	cspec
PM2	Met	Absent from gnomAD v2.1 and v4.1, meeting the PTEN VCEP PM2_Supporting threshold of <0.00001 (<0.001%) allele frequency.	gnomad_v2 gnomad_v4
PM5	Not assessed	A different missense at the same residue (N48K) is reported in PMID 14675182, but its ACMG/AMP classification is not established and full-text verification was unavailable. Without a confirmed P/LP comparator at residue N48, PM5 cannot be applied.
PM6	Not assessed	No assumed de novo observations for this variant were identified in the available evidence.
PP1	Not assessed	No co-segregation data was available for this variant.
PP2	Met	PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PHTS (PTEN Hamartoma Tumor Syndrome), satisfying the VCEP PP2 criterion.	cspec
PP3	Met	REVEL score of 0.919 exceeds the PTEN VCEP PP3 threshold of >0.7 for missense variants, supporting a deleterious effect.	revel
PP4	N/A	PTEN VCEP: phenotype specificity has been incorporated into the rule specifications for PS4 Use 2; PP4 is not applicable.	cspec
PP5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for PTEN.	cspec
BA1	Not met	Variant is absent from gnomAD v2.1 and v4.1; allele frequency of 0 does not exceed the VCEP BA1 threshold of >0.00056 (>0.056%).	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD; allele frequency does not fall within the VCEP BS1 range (0.0000043 to 0.00056).	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations of this variant in healthy or PHTS-unaffected individuals were identified; absent from gnomAD.	gnomad_v2 gnomad_v4
BS3	Not met	Mighell et al. 2018 functional assay Cum_score = -3.41 for N48T, which does not meet the BS3_Supporting threshold of >0; the variant shows a damaging rather than benign functional effect.	vcep_mmc2
BS4	Not assessed	No segregation data was available to evaluate lack of segregation in affected family members.
BP1	N/A	BP1 is not applicable to PTEN per the VCEP; missense variants are a common mechanism of disease in PTEN.	cspec
BP2	Not assessed	No observations of this variant in trans with a pathogenic or likely pathogenic PTEN variant, or in cis/phase-unknown with P/LP PTEN variants, were identified.
BP3	N/A	In-frame deletion/insertion criterion; this is a missense substitution.
BP4	Not met	REVEL score of 0.919 exceeds the VCEP BP4 threshold of <0.5 for missense variants, indicating computational evidence suggests impact rather than no impact.	revel
BP5	Not assessed	No cases with an alternate molecular basis for disease were identified for this variant, and at least two such cases are required by the VCEP.
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for PTEN.	cspec
BP7	N/A	BP7 applies to synonymous or intronic variants; this is a missense variant c.143A>C p.(Asn48Thr).
PM3	N/A	PM3 applies to recessive disorders; PTEN-associated PHTS is an autosomal dominant condition.	cspec
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants causing protein length changes; this is a missense substitution.

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