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.1 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.2 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.3
Final classification
VUS
BP4
HRAS
c.277A>G
p.Ile93Val
This variant
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.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: BP4 supporting; no rule matched the adjudicated criteria.
Classification rationale
BP4
VUS
HRAS c.277A>G
BP4
→
VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_176795.4 · variants mapped to exon structure
HRAS
NM_176795.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 16 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
BP4
supporting
Benign
Computational evidence supports a benign interpretation. REVEL is 0.141, which is below the BP4 threshold of 0.3 for missense variants, BayesDel is -0.349425, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.
REVEL score 0.141.BayesDel score -0.349425.SpliceAI max delta score 0.03.
Assessed · not applied
· 5 not met · 11 not assessed
Pathogenic
PS1
No previously established pathogenic variant causing the same amino acid change was identified, so PS1 cannot be applied from the available evidence.
PS2
No confirmed de novo occurrence with sufficient phenotype and parental testing details was identified, so PS2 cannot be applied.
PS3
Approved functional assay types are defined for HRAS, but no variant-specific approved functional result for p.(Ile93Val) was identified in the available evidence, so PS3 cannot be applied.
PS4
The available evidence does not establish the number of unrelated affected individuals or a point total required for PS4, so this criterion cannot be applied.
PM1
This variant affects codon 93, which is outside the HRAS RASopathy VCEP PM1 domains (P-loop amino acids 10-17, SW1 amino acids 25-40, SW2 amino acids 57-64, and SAK amino acids 145-156).
PM2
This variant is present in population databases, so it is not absent from controls and PM2 cannot be applied.
PM5
No established pathogenic missense change at the same codon or analogous residue position was identified in the available evidence, so PM5 cannot be applied.
PM6
No de novo occurrence without full parental confirmation was identified from the available evidence, so PM6 cannot be applied.
PP1
No segregation data were identified, so PP1 cannot be applied.
PP3
Available computational evidence does not meet the HRAS RASopathy VCEP threshold for PP3.
Benign
BA1
Population frequency is below the BA1 threshold.
BS1
Population frequency is below the BS1 threshold.
BS2
No data were identified showing this variant in sufficient unaffected individuals for BS2 scoring.
BS4
No lack-of-segregation data were identified, so BS4 cannot be applied.
BP2
No evidence was identified for this variant occurring with an alternative molecular cause in the same gene, so BP2 cannot be applied.
BP5
No alternative molecular diagnosis or clearly different explanatory cause was identified, so BP5 cannot be applied.
N/A · 11
PVS1 · PM3 · PM4 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This 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).
v2.1
This 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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,613,210
0 hom
0 hom
Remaining individuals 2 / 62,472 |
0.0032% |
European (Finnish) 2 / 63,238 |
0.0032% |
+ 8 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.00071%
· 2 / 282,578
0 hom
0 hom
Remaining individuals 1 / 7,218 |
0.014% |
European (Finnish) 1 / 25,120 |
0.004% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (non-Finnish), South Asian)
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.141. BayesDel score = -0.349425.
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
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).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links