BS1_Strong is met: the gnomAD v4.1 grpmax filtering allele frequency is 5.81e-05 (0.0058%), which falls within the PTEN VCEP BS1_Strong range of 0.0043%-0.056%. This population frequency is higher than expected for a fully penetrant pathogenic PTEN variant causing PHTS.1 BP7_Supporting is met: c.492+14dup is an intronic variant at position +14 (beyond +7). SpliceAI predicts no significant splice impact (max delta score 0.03) and no creation of a cryptic splice site, meeting the PTEN VCEP BP7 criteria.2 PM2_Supporting is not met: although the overall gnomAD allele frequency is very low (v4.1: 0.00025%), the Middle Eastern subpopulation in gnomAD v4.1 has 2 alleles out of 6,068 (AF 0.033%), which exceeds the PTEN VCEP subpopulation threshold of 0.002% for multiple alleles.3 PVS1 is not met: this intronic duplication at c.492+14 does not qualify as a null variant under the PTEN PVS1 decision tree, and SpliceAI predicts no splice disruption.4 Combined classification: 1 strong benign criterion (BS1) + 1 supporting benign criterion (BP7) yields a classification of Likely Benign per the ACMG/AMP combining rules adopted by the PTEN VCEP.5
PTEN
Final classification
Likely Benign
PTEN c.492+14dup · p.?
PTEN
BS1_Strong is met: the gnomAD v4.1 grpmax filtering allele frequency is 5.81e-05 (0.0058%), which falls within the PTEN VCEP BS1_Strong range of 0.0043%-0.056%. This population frequency is higher than expected for a fully penetrant pathogenic PTEN variant causing PHTS.
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule20 (1 Benign.Strong) with applied criteria: BS1 strong benign, BP7 supporting benign; maps to Likely Benign.
Classification rationale
BS1BP7
Likely Benign
PTEN c.492+14dup
BS1 + BP7
→
Likely Benign
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
4 / 1,601,512
0.00025%
Highest · Middle Eastern
0.033%
Homozygotes
0
grpmax FAF
0.0058%
Allele frequency by ancestry — gnomAD v4.1
observed in 2 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| Middle Eastern | 2 / 6,068 | 0.033% | 0 |
| European (non-Finnish) | 2 / 1,168,784 | 0.00017% | 0 |
| Admixed American | 0 / 59,952 | — | — |
| European (Finnish) | 0 / 63,996 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,792 | — | — |
| South Asian | 0 / 90,834 | — | — |
| Ashkenazi Jewish | 0 / 29,536 | — | — |
| African/African American | 0 / 74,588 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 2.49764e-06; MAF= 0.00025%, 4/1601512 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000329598; MAF= 0.03296%, 2/6068 alleles, homozygotes = 0); grpmax FAF= 5.813e-05.
Overall AF
1 / 250,646
0.0004%
Highest · European (non-Finnish)
0.00088%
Homozygotes
0
Allele frequency by ancestry — gnomAD v2.1
observed in 1 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 1 / 113,326 | 0.00088% | 0 |
| African/African American | 0 / 16,024 | — | — |
| Admixed American | 0 / 34,528 | — | — |
| Ashkenazi Jewish | 0 / 10,068 | — | — |
| East Asian | 0 / 18,370 | — | — |
| European (Finnish) | 0 / 21,638 | — | — |
| Remaining individuals | 0 / 6,088 | — | — |
| South Asian | 0 / 30,604 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 3.98969e-06; MAF= 0.00040%, 1/250646 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.8241e-06; MAF= 0.00088%, 1/113326 alleles, homozygotes = 0).
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 419168)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · 22 PMIDs triaged · 8 high-priority
22papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
23918944 ↗
splicing rna
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familia
BP7PP3PP5PS4PVS1
25741868 ↗
functional
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PS3PS4
12692171 ↗
case observation
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
As the leading organization representing cancer specialists involved in patient care and clinical research, the American Society of Clinical Oncology (ASCO) reaffirms its commitment to integrating cancer risk assessment and management, including molecular analysis of cancer predisposition genes, into the practice of oncology and preventive medicine. The primary goal of this effort is to foster exp
PP5PS4
15604628 ↗
case observation
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in
PP5PS4
17392385 ↗
case observation
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
New evidence on breast Magnetic Resonance Imaging (MRI) screening has become available since the American Cancer Society (ACS) last issued guidelines for the early detection of breast cancer in 2003. A guideline panel has reviewed this evidence and developed new recommendations for women at different defined levels of risk. Screening MRI is recommended for women with an approximately 20-25% or gre
PP5PS4
17508274 ↗
case observation
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial and ethical implications of identifying at-risk individuals for hereditary breast and ovarian cancer (HBOC) through cancer risk assessment, with or without genetic susceptibility testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors' Familial Cancer
PP5PS4
18163131 ↗
case observation
The emerging landscape of breast cancer susceptibility.
The genetic basis of inherited predisposition to breast cancer has been assiduously investigated for the past two decades and has been the subject of several recent discoveries. Three reasonably well-defined classes of breast cancer susceptibility alleles with different levels of risk and prevalence in the population have become apparent: rare high-penetrance alleles, rare moderate-penetrance alle
PP5PS4
19305347 ↗
case observation
ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.
Hereditary breast and ovarian cancer syndrome is an inherited cancer-susceptibility syndrome. The hallmarks of this syndrome are multiple family members with breast cancer or ovarian cancer or both, the presence of both breast cancer and ovarian cancer in a single individual, and early age of breast cancer onset. Clinical genetic testing for gene mutations allows physicians to more precisely ident
PP5PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links