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

Variant: NM_000314.6(PTEN):c.181C>G (p.His61Asp)

CA000330

7841 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 37398c37-6caa-4c1d-a1b1-3881be31e38b

HGVS expressions

NM_000314.6:c.181C>G
NM_000314.6(PTEN):c.181C>G (p.His61Asp)
NC_000010.11:g.87925529C>G
CM000672.2:g.87925529C>G
NC_000010.10:g.89685286C>G
CM000672.1:g.89685286C>G
NC_000010.9:g.89675266C>G
NG_007466.2:g.67091C>G
ENST00000686459.1:c.181C>G
ENST00000688158.1:c.*292C>G
ENST00000688308.1:c.181C>G
ENST00000688922.1:n.50C>G
ENST00000693560.1:c.700C>G
ENST00000371953.8:c.181C>G
ENST00000371953.7:c.181C>G
ENST00000498703.1:n.7C>G
ENST00000610634.1:c.79C>G
NM_000314.5:c.181C>G
NM_001304717.2:c.700C>G
NM_001304718.1:c.-541-5517C>G
NM_000314.7:c.181C>G
NM_001304717.5:c.700C>G
NM_001304718.2:c.-541-5517C>G
NM_000314.8:c.181C>G
NM_000314.8(PTEN):c.181C>G (p.His61Asp)

Likely Pathogenic

Met criteria codes 4
PS3 PP2 PM6 PM2
Not Met criteria codes 22
PS2 PS4 PS1 PP4 PP1 PP3 PM3 PM1 PM5 PM4 PVS1 BA1 BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP1 BP4 BP3

Evidence Links 4

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
PTEN VCEP
PTEN c.181C>G (p.His61Asp) 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). PS3: Phosphatase activity <50% of wild type (PMID 29706350, PMID 17942903, PMID 21828076) PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 11748304) 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
PS3
Variant demonstrated loss of function when analyzed in vivo in yeast. Variant demonstrated no activity in vivo and demonstrated low protein expression levels in yeast. Variant was strongly destabilized in MCF-7cells. Per Felicia, I agree.
Variant demonstrated loss of function when analyzed in vivo in yeast. PubMed:21828076
Variant demonstrated no activity in vivo and demonstrated low protein expression levels in yeast. Variant was strongly destabilized in MCF-7cells. PubMed:17942903
score -3.85 PubMed:29706350
PP2
PP2 applied because of low rate of benign missense variation. Per Felicia, I agree.
PM6
Reardon 2001.
Case report of a male patient identified during gestation as probably having a tracheooesophageal fistula, owing to polyhydramnios and an absent stomach bubble on ultrasonography. Macrocephaly and bilateral hand malformations noted at birth. Mutation analysis showed a de novo germline mutation, H61D, not present in either parent and paternity is confirmed. PubMed:11748304
PM2
Variant not present in population databases. Per Felicia, I agree.
Not Met criteria codes
PS2
Case report of a male patient identified during gestation as probably having a tracheooesophageal fistula, owing to polyhydramnios and an absent stomach bubble on ultrasonography. Macrocephaly and bilateral hand malformations noted at birth. Mutation analysis showed a de novo germline mutation, H61D, not present in either parent and paternity is confirmed. Per Felicia, I feel the the case in Reardon et al. should be PM6 since they didn't state whether maternity was confirmed. PM6 to be applied instead of PS2.
Case report of a male patient identified during gestation as probably having a tracheooesophageal fistula, owing to polyhydramnios and an absent stomach bubble on ultrasonography. Macrocephaly and bilateral hand malformations noted at birth. Mutation analysis showed a de novo germline mutation, H61D, not present in either parent and paternity is confirmed. PubMed:11748304
PS4
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
PP4
Patient phenotype information provided in paper does not meet a CC score or 4 or greater. Per Felicia, I agree.
Patient phenotype information provided in paper does not meet a CC score or 4 or greater. PubMed:11748304
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Variant is the incorrect variant type to apply these criteria.
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Variant does not occur within specified residues.
PM5
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
BA1
Variant not present in population databases. Per Felicia, I agree.
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
Variant demonstrated loss of function when analyzed in vivo in yeast. Variant demonstrated no activity in vivo and demonstrated low protein expression levels in yeast. Variant was strongly destabilized in MCF-7cells. Per Felicia, I agree.
BS1
Variant not present in population databases. Per Felicia, I agree.
BS2
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
BP7
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
BP1
PP2 applied because of low rate of benign missense variation. Per Felicia, I agree.
BP4
Variant is the incorrect variant type to apply these criteria.
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2021-06-04
Published on: 2022-09-30
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