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

Variant: NM_000314.6(PTEN):c.388C>G (p.Arg130Gly)

CA16602437

375958 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 1ff92475-1a3f-42b2-b733-1515bf2a4e10
Approved on: 2019-06-25
Published on: 2019-07-23

HGVS expressions

NM_000314.6:c.388C>G
NM_000314.6(PTEN):c.388C>G (p.Arg130Gly)
NC_000010.11:g.87933147C>G
CM000672.2:g.87933147C>G
NC_000010.10:g.89692904C>G
CM000672.1:g.89692904C>G
NC_000010.9:g.89682884C>G
NG_007466.2:g.74709C>G
NM_000314.5:c.388C>G
NM_001304717.2:c.907C>G
NM_001304718.1:c.-363C>G
NM_000314.7:c.388C>G
NM_001304717.5:c.907C>G
NM_001304718.2:c.-363C>G
ENST00000371953.7:c.388C>G
ENST00000498703.1:n.214C>G
ENST00000610634.1:c.286C>G
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Pathogenic

Met criteria codes 5
PM1 PM5 PM2 PS3 PP2
Not Met criteria codes 17
BP7 BP5 BP4 BP2 PM4 PVS1 PM6 PS4 PS2 PS1 BA1 PP3 PP1 BS1 BS3 BS4 BS2

Evidence Links 9

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
PTEN VCEP
PTEN c.388C>G (p.Arg130Gly) meets criteria to be classified as 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). PS3: Phosphatase activity <50% of wild type (PMID 10866302, PMID 21828076, PMID 29706350) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM2: Absent in large sequenced populations (PMID 27535533). PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 7829, SCV000840465.2). 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.
Met criteria codes
PM1
KS: Located in P-loop at residue 130. Agree MP
PM5
KS: Our VCEP curated R130Q as pathogenic. BLOSUM62 for R130Q = 1. BLOSUM62 for R130G = -2.
PM2
Variant not present in gnomAD. KS agrees.
PS3
Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN. Revealed no protein activity in figure 4. This variant is in the PTEN catalytic loop. He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant. Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable. Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot. Patient likely the same as patient analyzed in Xin He et al. paper. The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification. In contrast, Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. (MP submitted). KS agrees.
Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. PubMed:29785012
Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN. Revealed no protein activity in figure 4. This variant is in the PTEN catalytic loop. PubMed:21828076
Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot. Patient likely the same as patient analyzed in Xin He et al. paper. PubMed:19457929
PTEN missense mutations expressed them in Escherichia coli. The purified (His)6-tagged PTEN proteins were tested for their ability to dephosphorylate inositol 1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-triphosphate. R130G showed no phosphatase activities against Ins(1,3,4,5)P4. PubMed:10866302
The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification. PubMed:29706350
He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant. Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable. PubMed:20926450
PP2
KS agrees.
Not Met criteria codes
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
KS: Lots of somatic papers for this variant! Agree MP. GeneDx internal data: 7yo female with macrocephaly (5-6SD), lipoma, lip discoloration, facial telangiectasias, constipation, macrosomia (ht/wt+2.5-3SD). Does not meet PP4 since pediatric proband specificity score is 4. PTEN study data: Female, OFC = 58.5 cm, goiter, thyroid gland follicular adenoma, hashimoto disease, bilateral breast cancer dx 44, FCBD, intraductal papilloma of breast, uterine fibroids, lipoma, papilloma, skin tag, acral keratoses, CC score = 16.
Author and institution overlap. Likely same patient as Ngeow et al., 2014. PubMed:19457929
Author and institution overlap. Likely is the same patient as Ngeow et al., 2014. PubMed:25669429
Author and institution overlap. Likely is the same patient as Ngeow et al., 2014. PubMed:20926450
Paper reports 1 patient with no further details provided. PubMed:21659347
Female with primary breast cancer diagnosis at age 44 years. Second breast cancer. CC score = 16. MP agrees. Consider requesting more phenotype data? PubMed:24778394
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
KS: Matreyek WT-like range. MP agrees.
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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