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
v4.1
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.
v2.1
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).
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,601,512
0 hom · FAF 0.0058%
0 hom · FAF 0.0058%
Middle Eastern 2 / 6,068 |
0.033% |
European (non-Finnish) 2 / 1,168,784 |
0.00017% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 250,646
0 hom
0 hom
European (non-Finnish) 1 / 113,326 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
CLINVAR
25741868 ↗
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.
CLINVAR
12692171 ↗
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
17508274 ↗
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR