Variant: NM_000314.6(PTEN):c.722T>C (p.Phe241Ser)

CA000555

7850 (ClinVar)

Gene: PTEN

Condition: PTEN hamartoma tumor syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 5c047758-6fb8-4f71-9a53-077a7bf9a2c2

Approved on: 2023-06-14

Published on: 2023-10-19

HGVS expressions

NM_000314.6:c.722T>C
NM_000314.6(PTEN):c.722T>C (p.Phe241Ser)
NC_000010.11:g.87957940T>C
CM000672.2:g.87957940T>C
NC_000010.10:g.89717697T>C
CM000672.1:g.89717697T>C
NC_000010.9:g.89707677T>C
NG_007466.2:g.99502T>C
ENST00000686459.1:c.*308T>C
ENST00000688158.1:c.*833T>C
ENST00000688308.1:c.722T>C
ENST00000688922.1:c.643T>C
ENST00000693560.1:c.1241T>C
ENST00000371953.8:c.722T>C
ENST00000371953.7:c.722T>C
ENST00000472832.2:c.149T>C
NM_000314.5:c.722T>C
NM_001304717.2:c.1241T>C
NM_001304718.1:c.131T>C
NM_000314.7:c.722T>C
NM_001304717.5:c.1241T>C
NM_001304718.2:c.131T>C
NM_000314.8:c.722T>C
NM_000314.8(PTEN):c.722T>C (p.Phe241Ser)

Likely Pathogenic

• Met criteria codes: PP2 PP3 PS3_Moderate PM2_Supporting PS4_Supporting

• Not Met criteria codes: PP4 PP1 PM6 PS1 PS2 PM5 PM4 PM1 PM3 BA1 PVS1 BP7 BP5 BP3 BP1 BP4 BP2 BS1 BS3 BS4 BS2

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

Evidence submitted by expert panel

PTEN VCEP

NM_000314.8(PTEN):c.722T>C (p.Phe241Ser) variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. This variant: score of -2.39943 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID:15805158). PM2_P: 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 > 0.7 (score=0.858).

Met criteria codes

• 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 > 0.7 (score=0.858)
• PS3_Moderate: Functional studies supportive of a damaging effect on the gene or gene product. This variant: score of -2.39943 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350).
• PM2_Supporting: Absent in large sequenced populations in the gnomAD cohort. (PMID 27535533).
• PS4_Supporting: Proband(s) with phenotype specificity score of 1-1.5. (PMID:15805158). 2.5yo male with overgrowth, DD, autistic features, extreme macrocephaly (+4-4.5SD) and penile freckling. Peds score = 8, 1 PP4 point.

Not Met criteria codes

• PP4: Moved to PS4.
• PP1: 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
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: BUT F241L might get to PATH based on de novo observations per Yuen 2017. May need to curate.
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: Variant not within specified residues to apply criteria.
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: Absent in gnomAD; coverage looks good.
• PVS1: 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
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: Applying PP2 because of low rate of benign missense variation.
• 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
• BS1: Absent in gnomAD; coverage looks good.
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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