An RNA study has shown that NM_000314.8:c.253+5G>A causes exon 4 skipping, resulting in the predicted frameshift transcript consequence p.(Ala72Thrfs*5).1 Under the PTEN-specific PVS1 decision tree, a splice alteration that disrupts the reading frame in biologically relevant transcript NM_000314.8 and lies 5′ to p.D375 (c.1121) meets PVS1 at very strong strength; exon 4 skipping to p.(Ala72Thrfs*5) is consistent with this rule.2 The variant is absent from gnomAD v2.1 and is observed at 0/1,448,024 alleles in gnomAD v4.1, with 0/33,128 alleles in the highest observed subpopulation, which is below the PTEN PM2 thresholds of 0.001% overall and 0.002% within any subpopulation and supports PM2_Supporting.3 With PVS1 and PM2_Supporting under the PTEN VCEP framework, NM_000314.8:c.253+5G>A is classified as likely pathogenic.4
PTEN
Final classification
Likely Pathogenic
PTEN c.253+5G>A · p.?
PTEN
An RNA study has shown that NM_000314.8:c.253+5G>A causes exon 4 skipping, resulting in the predicted frameshift transcript consequence p.(Ala72Thrfs*5).
ACMG/AMP classification using ClinGen PTEN VCEP specifications v3.2.0
Classification rationale
PVS1PM2
Likely Pathogenic
PTEN c.253+5G>A
PVS1 + PM2
→
Likely Pathogenic
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 pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1448024 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/33128 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,448,024
0 hom
0 hom
Not observed in any ancestry group.
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Middle Eastern, European (non-Finnish), South Asian, Ashkenazi Jewish, East Asian, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.81).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV64300202, n = 2 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:28677221
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
Sources & reference links