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LYFE SCIENCES
Project: HERA
NM_176795.4:c.277A>G
p.Ile93Val  ·  HRAS
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Classification rationale
1

The HRAS c.277A>G (p.Ile93Val) variant has been observed in somatic cancer once in COSMIC and has been reported in ClinVar with conflicting germline interpretations, including an expert-panel classification of uncertain significance.

clinvar ↗ PMID:28492532 ↗
2

This variant is present at very low frequency in population databases, with 2/282578 alleles in gnomAD v2.1 (0.00071%) and 4/1613210 alleles in gnomAD v4.1 (0.00025%), which is below the HRAS RASopathy BS1 threshold of 0.025% and below the BA1 threshold of 0.05%, but it is not absent from controls.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Computational predictors do not support a damaging effect: REVEL is 0.141, BayesDel is -0.349425, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, supporting BP4 and not meeting the PP3 threshold.

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= 7.07769e-06; MAF= 0.00071%, 2/282578 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138543; MAF= 0.01385%, 1/7218 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.47953e-06; MAF= 0.00025%, 4/1613210 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20143e-05; MAF= 0.00320%, 2/62472 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. HRAS, a GTPase, is altered in a diverse range of cancers including head and neck squamous cell carcinoma, thyroid, and bladder cancer.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.141. BayesDel score = -0.349425.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104539846, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueI93
Hotspots ↗