About HRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
HRAS c.277A>G, p.(Ile93Val)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen HRAS VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: 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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
4 / 1,613,210 alleles
gnomAD v4.1: 4 / 1,613,210 alleles. Recorded AF 2.47953e-06. Recorded homozygote count 0.
gnomAD 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).
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen HRAS VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 5 not met · 11 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
No criteria match.
Met · 1
BP4 SupportingComputational 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. Details ▾Hide ▴
Rule
For missense variants, BP4 applies when REVEL ≤0.3.
Evidence considered
- REVEL score 0.141.
- BayesDel score -0.349425.
- SpliceAI max delta score 0.03.
Sources
Not met · 5 · evaluated, threshold not reached
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). Cancer Hotspots also did not identify this residue as a statistically significant hotspot. Details ▾Hide ▴
Rule
PM1 applies only to P-loop 10-17, SW1 25-40, SW2 57-64, or SAK 145-156.
Evidence considered
- Ile93 lies outside the VCEP PM1 domain intervals.
- Cancer Hotspots review did not show a significant hotspot at I93.
Sources
PM2 This variant is present in population databases, so it is not absent from controls and PM2 cannot be applied. It is seen in gnomAD v2.1 at 2/282578 alleles (AF 0.00071%) and in gnomAD v4.1 at 4/1613210 alleles (AF 0.00025%). Details ▾Hide ▴
Rule
PM2_Supporting requires absence from gnomAD.
Evidence considered
- gnomAD v2.1 total AF 7.077691823142637e-06 (0.00071%)
- AC 2/282578.
- gnomAD v4.1 total AF 2.4795283936995185e-06 (0.00025%)
- AC 4/1613210.
Sources
PP3 Available computational evidence does not meet the HRAS RASopathy VCEP threshold for PP3. REVEL is 0.141, which is below the PP3 threshold of 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03. Details ▾Hide ▴
Rule
For missense variants, PP3 requires REVEL ≥0.7.
Evidence considered
- REVEL score 0.141.
- SpliceAI max delta score 0.03.
Sources
BA1 Population frequency is below the BA1 threshold. The highest observed gnomAD subpopulation frequency is 0.01385% in v2.1 and 0.00320% in v4.1, both below the BA1 threshold of 0.05%. Details ▾Hide ▴
Rule
BA1 requires gnomAD filtering allele frequency ≥0.05%.
Evidence considered
- gnomAD v2.1 highest subpopulation AF 0.00013854253255749516 (0.01385%).
- gnomAD v4.1 highest subpopulation AF 3.201434242540658e-05 (0.00320%).
Sources
BS1 Population frequency is below the BS1 threshold. The highest observed gnomAD subpopulation frequency is 0.01385% in v2.1 and 0.00320% in v4.1, both below the BS1 threshold of 0.025%. Details ▾Hide ▴
Rule
BS1 requires gnomAD filtering allele frequency ≥0.025%.
Evidence considered
- gnomAD v2.1 highest subpopulation AF 0.00013854253255749516 (0.01385%).
- gnomAD v4.1 highest subpopulation AF 3.201434242540658e-05 (0.00320%).
Sources
Not assessed · 11 · no assessment recorded
PS1 No previously established pathogenic variant causing the same amino acid change was identified, so PS1 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant.
Evidence considered
- No same-amino-acid pathogenic comparator was identified in the available case materials.
Still missing
- Confirmation of whether another nucleotide change causing p.(Ile93Val) has been established as pathogenic in the approved HRAS/RASopathy framework.
Sources
PS2 No confirmed de novo occurrence with sufficient phenotype and parental testing details was identified, so PS2 cannot be applied. Details ▾Hide ▴
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. Details ▾Hide ▴
Rule
One approved assay supports PS3_Supporting; two or more different approved assays support PS3_Moderate.
Evidence considered
- RASopathy VCEP approved assay classes include RAS activation
- MEK activation
- and ERK activation.
- No variant-specific reviewed functional evidence was identified for this variant in the retrieved materials.
Still missing
- Variant-specific results from one or more approved assays such as RAS activation
- MEK activation
- or ERK activation.
Sources
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. Details ▾Hide ▴
Rule
Point-based affected-individual scoring per HRAS RASopathy VCEP.
Evidence considered
- ClinVar shows conflicting submissions and an expert-panel VUS classification
- but the available materials do not provide a verified affected-case count for PS4 scoring.
Still missing
- Unique proband count and phenotype specificity needed for VCEP point-based PS4 scoring.
Sources
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. Details ▾Hide ▴
Rule
PM5 applies to established pathogenic missense change at the same codon; stronger use requires additional same-codon evidence.
Evidence considered
- No qualifying same-codon pathogenic comparator was identified in the case materials.
Still missing
- Confirmed same-codon or approved analogous-residue pathogenic comparator under the HRAS/RASopathy specification.
Sources
PM6 No de novo occurrence without full parental confirmation was identified from the available evidence, so PM6 cannot be applied. Details ▾Hide ▴
PP1 No segregation data were identified, so PP1 cannot be applied. Details ▾Hide ▴
BS2 No data were identified showing this variant in sufficient unaffected individuals for BS2 scoring. Details ▾Hide ▴
Rule
Point-based BS2 scoring per HRAS RASopathy VCEP.
Evidence considered
- No qualifying unaffected-carrier evidence was available.
Still missing
- Well-phenotyped unaffected carriers or point-based benign evidence under the HRAS RASopathy framework.
Sources
BS4 No lack-of-segregation data were identified, so BS4 cannot be applied. Details ▾Hide ▴
BP2 No evidence was identified for this variant occurring with an alternative molecular cause in the same gene, so BP2 cannot be applied. Details ▾Hide ▴
BP5 No alternative molecular diagnosis or clearly different explanatory cause was identified, so BP5 cannot be applied. Details ▾Hide ▴
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the HRAS RASopathy specification marks PVS1 as not applicable. Available PVS1 context does not support use of a null-variant mechanism for this variant type. Details ▾Hide ▴
Rule
HRAS RASopathy VCEP: PVS1 not applicable.
Evidence considered
- HRAS RASopathy VCEP marks PVS1 not applicable.
- NM_176795.4:c.277A>G produces p.(Ile93Val)
- not a truncating or canonical splice variant.
Sources
PM3 N/APM3 is not applicable in the HRAS RASopathy specification. Details ▾Hide ▴
Rule
PM3 not applicable.
Evidence considered
- HRAS RASopathy VCEP marks PM3 not applicable.
Sources
PM4 N/AThis is a missense variant and does not cause an in-frame length change or stop-loss, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 applies to in-frame insertions/deletions or stop-loss variants.
Evidence considered
- NM_176795.4:c.277A>G results in p.(Ile93Val).
Sources
PP2 N/APP2 is not applicable in the HRAS RASopathy specification. Details ▾Hide ▴
Rule
PP2 not applicable.
Evidence considered
- HRAS RASopathy VCEP marks PP2 not applicable.
Sources
PP4 N/APP4 is not applicable in the HRAS RASopathy specification. Details ▾Hide ▴
Rule
PP4 not applicable; see PS4.
Evidence considered
- HRAS RASopathy VCEP marks PP4 not applicable.
Sources
PP5 N/APP5 is not used in this VCEP framework. Details ▾Hide ▴
Rule
PP5 not for use.
Evidence considered
- HRAS RASopathy VCEP marks PP5 not applicable.
Sources
BS3 N/ABS3 is not applicable in the HRAS RASopathy specification. Details ▾Hide ▴
Rule
BS3 not applicable.
Evidence considered
- HRAS RASopathy VCEP marks BS3 not applicable.
Sources
BP1 N/ABP1 in this framework is intended for truncating loss-of-function variants in genes with primarily gain-of-function disease mechanisms. This variant is missense, so BP1 is not applicable. Details ▾Hide ▴
Rule
BP1 applies to truncating loss-of-function variants in this framework.
Evidence considered
- NM_176795.4:c.277A>G is a missense variant.
Sources
BP3 N/ABP3 is not applicable in the HRAS RASopathy specification. Details ▾Hide ▴
Rule
BP3 not applicable.
Evidence considered
- HRAS RASopathy VCEP marks BP3 not applicable.
Sources
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
Rule
BP6 not for use.
Evidence considered
- HRAS RASopathy VCEP marks BP6 not applicable.
Sources
BP7 N/ABP7 applies to synonymous or certain noncoding variants with no predicted splice impact. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous/noncoding variants with no predicted splice impact.
Evidence considered
- NM_176795.4:c.277A>G results in p.(Ile93Val).
- SpliceAI max delta score 0.03.
Sources
Identifiers
- Gene
- HRAS
- Transcript
- NM_176795.4
- Coding (HGVS c.)
- NM_176795.4:c.277A>G
- Protein (HGVS p.)
- NP_789765.1:p.(Ile93Val)
- GRCh38
- chr11:533779 T>C
- GRCh37
- chr11:533779 T>C
Gene diagram
Every interpreted variant in HRAS, mapped onto the exon structure of NM_176795.4. Select a row to find it on the plot.
HRASNM_176795.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in HRAS
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
4 / 1,613,210 alleles
AF 2.48e-06 · 0 homozygotes
gnomAD v2.1
2 / 282,578 alleles
AF 7.08e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,613,210 alleles · 0 hom
| Remaining individuals2 / 62,472 | 3.2e-05 |
| European (Finnish)2 / 63,238 | 3.2e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 7.1e-06 · 2 / 282,578 alleles · 0 hom
| Remaining individuals1 / 7,218 | 0.00014 |
| European (Finnish)1 / 25,120 | 4e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (non-Finnish), South Asian.
Statements
gnomAD 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).
gnomAD 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).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingComputational 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. Details ▾Hide ▴
Rule
For missense variants, BP4 applies when REVEL ≤0.3.
Evidence considered
- REVEL score 0.141.
- BayesDel score -0.349425.
- SpliceAI max delta score 0.03.
Sources
PP3 Available computational evidence does not meet the HRAS RASopathy VCEP threshold for PP3. REVEL is 0.141, which is below the PP3 threshold of 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03. Details ▾Hide ▴
Rule
For missense variants, PP3 requires REVEL ≥0.7.
Evidence considered
- REVEL score 0.141.
- SpliceAI max delta score 0.03.
Sources
BP7 N/ABP7 applies to synonymous or certain noncoding variants with no predicted splice impact. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous/noncoding variants with no predicted splice impact.
Evidence considered
- NM_176795.4:c.277A>G results in p.(Ile93Val).
- SpliceAI max delta score 0.03.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.141. BayesDel score = -0.349425.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
4 / 1,613,210 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243116
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/40439/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-533779-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-533779-T-C?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_176795.4%3Ac.277A…
- OncoKB ↗www.oncokb.org/gene/HRAS/I93V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=140205027
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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).
gnomAD 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).
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104539846, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.