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PTEN
Final classification
VUS
PTEN c.165-7T>C · p.?
PTEN

NM_000314.8:c.165-7T>C is an intronic variant in PTEN located at position -7 of the intron 2 splice acceptor region.

Gene
PTEN
Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.165-7T>C
Consequence
N/A
GRCh38
chr10:87925506 T>C
GRCh37
chr10:89685263 T>C
Basis Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BS1 strong benign; no rule matched the adjudicated criteria.
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BS1 strong benign; no rule matched the adjudicated criteria.
Classification rationale
BS1 VUS
PTEN c.165-7T>C

NM_000314.8:c.165-7T>C is an intronic variant in PTEN located at position -7 of the intron 2 splice acceptor region. This variant is present in gnomAD v4.1 at a grpmax filtering allele frequency of 0.006% (11/1,587,106 alleles), which falls within the PTEN VCEP BS1_Strong range (0.0043%-0.056%), indicating the variant is observed at a population frequency greater than expected for a highly penetrant autosomal dominant disorder.1 The variant is classified as Likely benign in ClinVar (VCV000412808) by 5 clinical laboratories, consistent with the population frequency evidence.2 SpliceAI predicts no significant splicing impact (max delta score = 0.02), which falls within the benign range for computational splice prediction but is not sufficient alone to apply BP4 under the PTEN VCEP without VarSeak concordance.3 No pathogenic computational predictions, functional assay data, segregation evidence, de novo observations, or case-level phenotype data were identified to support pathogenicity for this variant. The variant does not meet PM2 under PTEN VCEP rules because the South Asian subpopulation frequency (0.0111%) exceeds the VCEP subpopulation threshold of 0.002%.4

BS1 VUS
Gene diagram · NM_000314.8 · variants mapped to exon structure
PTEN NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 16 assessed
Applied · 1
Strength Supporting Moderate Strong Very strong
BS1 strong Benign
PTEN VCEP v3.2.0 BS1_Strong applies when gnomAD filtering allele frequency is between 0.0043% (0.000043) and 0.056% (0.00056). The gnomAD v4.1 grpmax filtering allele frequency for this variant is 5.997e-05 (0.006%), which falls within the BS1_Strong range. This indicates the variant is observed at a population frequency greater than expected for a highly penetrant autosomal dominant disorder like PTEN hamartoma tumor syndrome.
gnomAD v4.1 grpmax FAF = 5.997e-05 (0.006%)within PTEN VCEP BS1_Strong range (0.0043%-0.056%)11 total alleles across 1
Assessed · not applied
Pathogenic
PVS1 The variant NM_000314.8:c.165-7T>C is an intronic substitution at position -7, which is not a canonical GT-AG ±1 or ±2 splice site.
PS1 No previously established pathogenic variant has been identified at the same nucleotide position (c.165-7) in PTEN.
PS2 No de novo observations (confirmed or assumed) were identified for NM_000314.8:c.165-7T>C in the available evidence.
PS3 No RNA, mini-gene, or other splicing assay data are available for this intronic variant.
PS4 No proband counts or case-control data with PTEN phenotype specificity scores are available for this variant.
PM2 Under PTEN VCEP v3.2.0, PM2_Supporting requires total gnomAD allele frequency <0.001% (0.00001) AND subpopulation AF <0.002% (0.00002) when multiple alleles are present.
PM6 No assumed or confirmed de novo observations were identified for this variant in the available evidence.
PP1 No co-segregation data are available for this variant.
PP3 Under PTEN VCEP v3.2.0, PP3 for splicing variants requires concordance of SpliceAI (scores 0.5-1, pathogenic range) and VarSeak (Class 4-5).
Benign
BA1 PTEN VCEP v3.2.0 BA1 requires gnomAD filtering allele frequency >0.056% (0.00056).
BS2 PTEN VCEP v3.2.0 BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual.
BS3 No RNA, mini-gene, or other splicing assay data demonstrating no splicing impact are available for this intronic variant.
BS4 No segregation data demonstrating lack of segregation in affected family members are available for this variant.
BP2 No observations of this variant in trans with a pathogenic or likely pathogenic PTEN variant, nor three or more observations in cis/phase-unknown with different P/LP PTEN variants, were identified in the available evidence.
BP4 PTEN VCEP v3.2.0 BP4 requires concordance of BOTH SpliceAI (scores 0-0.2 considered benign) AND VarSeak (Class 1-2 considered benign) predicting no splicing impact.
BP5 PTEN VCEP v3.2.0 BP5 requires at least two cases where the variant is found in individuals with an alternate molecular basis for disease, where the other gene/disorder is highly penetrant and there is no phenotypic overlap with PTEN.
N/A · 11 PM1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.93085e-06; MAF= 0.00069%, 11/1587106 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000110978; MAF= 0.01110%, 10/90108 alleles, homozygotes = 0); grpmax FAF= 5.997e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.2304e-06; MAF= 0.00042%, 1/236384 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.34986e-05; MAF= 0.00335%, 1/29852 alleles, homozygotes = 0).
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00069% · 11 / 1,587,106
0 hom · FAF 0.006%
South Asian
10 / 90,108
0.011%
Remaining individuals
1 / 61,718
0.0016%
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.00042% · 1 / 236,384
0 hom
South Asian
1 / 29,852
0.0033%
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories). (ClinVarID = 412808)
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
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.
COSMIC ↗
Sources & reference links
7Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
SpliceAI
OncoKB
COSMIC
Triaged references · 9 PMIDs not cited in assessment
25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. 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
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
20301661 ↗ PTEN Hamartoma Tumor Syndrome. CLINVAR
23519317 ↗ Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. CLINVAR
23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR
24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR