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LYFE SCIENCES
Project: HERA
NM_007294.4:c.135-1G>T
p.?  ·  BRCA1
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Classification rationale
1

The BRCA1 c.135-1G>T (NP_009225.1:p.?) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar with a pathogenic expert-panel classification.

clinvar ↗
2

This variant is present at very low frequency in population databases, with gnomAD v2.1 AF 7.14e-06 (2/280296 alleles) and gnomAD v4.1 AF 4.42e-06 (7/1583254 alleles), which is below benign frequency thresholds but does not meet the ENIGMA PM2 requirement for absence from controls.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

RNA and multifactorial evidence support a damaging splice effect for this variant, including exon 5 deletion in splicing studies, ENIGMA assignment of PVS1 (RNA), a reference-set posterior probability of 0.99999838416, and a BRCA1 clinical-history likelihood ratio of 59.69 across 7 probands, supporting PP4_Strong.

PMID:20020529 ↗ PMID:31853058 ↗
4

In silico splicing analysis predicts a strong splice effect, with a SpliceAI maximum delta score of 0.86, which is consistent with disruption of normal splicing but is not counted separately as PP3 because the same splice evidence is already captured under the PVS1 framework.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 7.13531e-06; MAF= 0.00071%, 2/280296 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56177e-05; MAF= 0.00156%, 2/128060 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 4.42127e-06; MAF= 0.00044%, 7/1583254 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.06741e-06; MAF= 0.00061%, 7/1153704 alleles, homozygotes = 0); grpmax FAF= 2.52e-06.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (17 clinical laboratories) and as pathogenic (1 clinical laboratory) and as not provided (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
03
Functional
No functional summary recorded.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.86).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV100524937, n = 1 times).
COSMIC ↗
06
Cancer hotspots
No cancer hotspot summary recorded.