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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_000314.6(PTEN):c.320A>T (p.Asp107Val)

CA16042748

372481 (ClinVar)

Gene: PTEN
Condition: PTEN hamartoma tumor syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: af7069ee-474b-491e-9317-5e91eeba5b76
Approved on: 2019-06-25
Published on: 2019-07-23

HGVS expressions

NM_000314.6:c.320A>T
NM_000314.6(PTEN):c.320A>T (p.Asp107Val)
NC_000010.11:g.87933079A>T
CM000672.2:g.87933079A>T
NC_000010.10:g.89692836A>T
CM000672.1:g.89692836A>T
NC_000010.9:g.89682816A>T
NG_007466.2:g.74641A>T
NM_000314.5:c.320A>T
NM_001304717.2:c.839A>T
NM_001304718.1:c.-431A>T
NM_000314.7:c.320A>T
NM_001304717.5:c.839A>T
NM_001304718.2:c.-431A>T
ENST00000371953.7:c.320A>T
ENST00000498703.1:n.146A>T
ENST00000610634.1:c.218A>T

Pathogenic

Met criteria codes 6
PM6 PM2 PS4_Moderate PS3 PP1 PP2
Not Met criteria codes 16
PM1 PM4 PM5 BA1 BS2 BS3 BS4 BS1 BP5 BP7 BP2 BP4 PVS1 PS2 PS1 PP3

Evidence Links 5

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
PTEN VCEP
PTEN c.320A>T (p.Asp107Val) 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 29706350) 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 25418537) PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 28526761, PMID 23886400, internal laboratory contributor SCV000490750.2) PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 28526761, PMID 23886400, internal laboratory contributor SCV000490750.2) 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
PM6
Variant occurred de novo in a child in the autism simplex cohort; methods appear to have been targeted to known candidate genes, not exome-based, but paper notes "paternity firmly established" via other variant info. May review with team to see whether would wish to apply PM6 or PS2. KS: Agrees and suggests applying PM6.
PubMed:25418537
PM2
absent gnomAD. KS agrees.
PS4_Moderate
1 GDx internal case with peds score = 6, 1 phenotype point; in addition to other lit reports, 2.5 points total, moderate evidence. KS agrees.
Variant in pt PC0018: 19yo M with extreme macrocephaly, evaluated at age 17yrs (62.5cm, +5.6SD at 17 yrs), autism/ID, thyroid nodules, penile freckling, 1 oral papilloma, clinical dx of CS. Peds score = 13, 1 phenotype point. PubMed:28526761
Proband had glycogenic acanthosis of the esophagus, keratosis of the hands and of the feet and juvenile polyps. He later developed a metastatic and locally advanced rectal cancer and hamartomatous small stomach polyps. minimum CC score = 27, 0.5 phenotype points. Daughter also positive for variant (but age unknown), her hx includes hamartomatous colon polyps since the age of 10. She was also affected by Hashimoto disease and arteriovenous malformation and showed small facial keratosis. PubMed:23886400
Seen de novo in 4yo M with autism and macrocephaly +3.44SD, no other features noted. No phenotype points. PubMed:25418537
PS3
KS agrees.
Variant showed low protein abundance (score 0.17), PS3 already applied to phosphatase data. PubMed:29785012
Variant showed truncation-like phosphatase activity (score -2.85) PubMed:29706350
PP1
3 meioses total (1 Paparo, 1 Hansen-Kiss, 1 GDx internal family)
Variant in pt PC0018: M with extreme macrocephaly, evaluated at age 17yrs (62.5cm, +5.6SD at 17 yrs), autism/ID, thyroid nodules, penile freckling, 1 oral papilloma, clinical dx of CS. Variant inherited from mother with macrocephaly (60.5cm), Hashimoto's and thyroid nodules, breast cancer dx @40y, multiple polyps. 1 meiosis. PubMed:28526761
Variant identified in proband described in PS4 section, variant also present in his daughter with hamartomatous colon polyps since the age of 10. She was also affected by Hashimoto disease and arteriovenous malformation and showed small facial keratosis. 1 meiosis. PubMed:23886400
PP2
KS agrees.
Not Met criteria codes
PM1
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
PM5
KS: D107N, D107G, D107Y are present in HGMD, however already meets pathogenic so not necessary to work these up.
BA1
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
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
Variant in pt PC0018: M with extreme macrocephaly, evaluated at age 17yrs (62.5cm, +5.6SD at 17 yrs), autism/ID, thyroid nodules, penile freckling, 1 oral papilloma, clinical dx of CS. Variant inherited from mother with macrocephaly (60.5cm), Hashimoto's and thyroid nodules, breast cancer dx @40y, multiple polyps. 1 meiosis. PubMed:28526761
Variant identified in proband described in PS4 section, variant also present in his daughter with hamartomatous colon polyps since the age of 10. She was also affected by Hashimoto disease and arteriovenous malformation and showed small facial keratosis. 1 meiosis. PubMed:23886400
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
GeneDx internal data: Patient with PALB2 variant.
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
BP4
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
PS2
PubMed:25418537
PS1
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
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