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
HRAS
Final classification
VUS
HRAS c.277A>G · p.Ile93Val
HRAS
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
Gene diagram
· NM_176795.4 · variants mapped to exon structure
HRAS
NM_176795.4
Fetching transcript structure from UCSC…
Applied criteria · 1 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
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