Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000314.8(PTEN):c.59G>T (p.Gly20Val)

CA377781994

428266 (ClinVar)

Gene: PTEN (HGNC:5728)

Condition: PTEN hamartoma tumor syndrome (MONDO:0017623)

Inheritance Mode: Autosomal dominant inheritance

UUID: fcbc972e-ad73-404c-ae8e-7cedfd4ec264

Approved on: 2023-08-04

Published on: 2023-10-19

HGVS expressions

NM_000314.8(PTEN):c.59G>T (p.Gly20Val)

NM_000314.8:c.59G>T

NC_000010.11:g.87864528G>T

CM000672.2:g.87864528G>T

NC_000010.10:g.89624285G>T

CM000672.1:g.89624285G>T

NC_000010.9:g.89614265G>T

NG_007466.2:g.6090G>T

NG_033079.1:g.3910C>A

ENST00000686459.1:c.59G>T

ENST00000688158.1:c.59G>T

ENST00000688308.1:c.59G>T

ENST00000693560.1:c.578G>T

ENST00000371953.8:c.59G>T

ENST00000371953.7:c.59G>T

ENST00000462694.1:n.61G>T

ENST00000487939.1:n.80G>T

ENST00000610634.1:c.-44G>T

ENST00000618586.1:n.28G>T

NM_000314.5:c.59G>T

NM_000314.6:c.59G>T

NM_001304717.2:c.578G>T

NM_001304718.1:c.-647G>T

NM_000314.7:c.59G>T

NM_001304717.5:c.578G>T

NM_001304718.2:c.-647G>T

Likely Pathogenic

PP3 PP2 PS2 PS4_Supporting PM2_Supporting

PM1 PM5 PS3

Evidence Links 0

Expert Panel

PTEN VCEP

Criteria Specification Information

Criteria Specification: ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

PTEN VCEP

NM_000314.8(PTEN):c.59G>T (p.Gly20Val) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history (Internal laboratory contributor(s) SCV001393771.3). PS4_P: Proband(s) with phenotype specificity score of 1-1.5 Internal laboratory contributor(s) SCV001393771.3). PM2_Supporting: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score = 0.931.

PP3

REVEL score = 0.931 (>0.75). From the REVEL home page, I downloaded the genome segment file "Chromosome 10: 074894550 - 094291662" to check/get the REVEL score (Matt J.).

PP2

This is a missense variant.

PS2

From Invitae: This variant has been observed to be de novo in an individual with features consistent with a PTEN-related condition (Invitae). ClinVar contains an entry for this variant (Variation ID: 428266). INTERNAL OBSERVATION: a child reported to have macrocephaly, lipoma, and gross motor delays. Parental testing done at Invitae confirmed relatedness and de novo status.

PS4_Supporting

Invitae: A child (< 10 yo) reported to have macrocephaly, lipoma, and gross motor delays (Ped score = 5).

PM2_Supporting

Absent in gnomAD. Updated from moderate to supporting level of evidence.

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

G20E: 1 ClinVar entry (VUS - GeneDx). Not curated by EP at this time, functional evidence found, possible cases; even if G20E was pathogenic, then G20V would still not meet likely pathogenic with applying PM5. BLOSUM = -2 (greater than G20E BLOSUM: -3). G20A: 1 ClinVar entry (VUS - Invitae). Not curated by EP at this time, functional evidence suggests this variant to impact function; even if G20E was pathogenic, then G20V would still not meet likely pathogenic with applying PM5. BLOSUM = 0 (greater than G20E BLOSUM: -3).

PS3

Mighell et al (2018) {29706350}: High confidence variant, cum_score = -0.9465 (> -1.11 threshold).

Curation History

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