The HRAS NM_005343.4:c.37G>C (NP_005334.1:p.(Gly13Arg)) missense variant has previously been reported in somatic cancers (COSMIC; COSV54236651, n = 466 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: HRAS c.37G>C showed abnormal active HRAS-GTP and ERK1/2 phosphorylation in two approved assay types, although the VCEP table lacks an exact-variant pre-assigned entry. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
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About HRAS
HRAS is a membrane-associated GTPase that acts as a molecular switch in cell signaling, cycling between active and inactive states as it binds and hydrolyzes GTP. It belongs to the RAS family of proto-oncogenes and helps transmit growth and survival signals through pathways such as MAPK and PI3K. Germline mutations in HRAS cause Costello syndrome, a developmental disorder marked by distinctive facial features, growth and cognitive problems, and a predisposition to tumors. Somatic HRAS mutations also drive many cancers, including cancers of the thyroid, bladder, and salivary glands.
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01The reasoning
How it was classified
The recorded framework is ClinGen HRAS VCEP v2.3. 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.
Met at Moderate: HRAS c.37G>C showed abnormal active HRAS-GTP and ERK1/2 phosphorylation in two approved assay types, although the VCEP table lacks an exact-variant pre-assigned entry.
PM1Moderate
PM1 · moderate
Met at moderate: HRAS residue 13 falls within the VCEP-approved P-loop domain spanning amino acids 10-17.
PM2Supporting
PM2 · supporting
Met at Supporting: the variant is absent from both gnomAD v2.1 and v4.1, satisfying the VCEP's requirement for absence from gnomAD controls.
PP3Supporting
PP3 · supporting
Met: REVEL score 0.791 meets the VCEP missense PP3 threshold of ≥0.7.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
VUS: PS3 and PM1 are moderate, while PM2 and PP3 are supporting; the HRAS VCEP's exact criteria-combination rules do not yield a classification.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
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.
ACMG/AMP criteria under ClinGen HRAS VCEP v2.3, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 3 not met · 10 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PM1 is met at Moderate strength because HRAS residue 13 lies in the VCEP-approved P-loop domain (AA 10-17).
PS1 and PM5 remain not assessed because the available evidence does not establish the required alternate-nucleotide same-amino-acid or alternate-residue same-codon comparators.
PP2 is explicitly not applicable in the HRAS VCEP specification, and BP1 is not applicable because the variant is missense rather than truncating.
PS3 is met at Moderate strength because PMID:22683711 reports abnormal HRAS-GTP activation and ERK1/2 phosphorylation for HRAS c.37G>C using two VCEP-approved assay types; BS3 is not applicable under the VCEP specification.
Only PS4, PP4, PP5, BP5, and BP6 were adjudicated.
PS4 was not assessed because the variant-positive reports are somatic lesion studies without affected-versus-unaffected case-control counts or a clearly qualifying VCEP alternative-path point total; no OR or 95% CI was computed because required control counts were unavailable.
PP4, PP5, and BP6 are not applicable under the HRAS VCEP's explicit CSPEC entries.
BP5 was not assessed because no alternative molecular cause or VCEP BP5 point assignment is documented.
PP3 is met at Supporting strength because the VCEP-named missense predictor, REVEL, is 0.791 versus the ≥0.7 threshold.
BP4 is not met because the VCEP missense REVEL cutoff is ≤0.3 and the score is 0.791.
BP7 is not_applicable because the variant is missense and outside the VCEP's synonymous, noncanonical intronic, and non-coding scope.
No criteria match.
Met · 4
PS3ModerateVCEPMet at Moderate: HRAS c.37G>C showed abnormal active HRAS-GTP and ERK1/2 phosphorylation in two approved assay types, although the VCEP table lacks an exact-variant pre-assigned entry.
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Reasoning
PS3 is met at Moderate strength. PMID:22683711 directly tested HRAS c.37G>C (p.Gly13Arg) using two distinct functional assay types that are listed as approved by the RASopathy VCEP: RAS activation measured by Raf1-RBD precipitation of active HRAS-GTP and ERK activation measured by ERK1/2 phosphorylation. Mutant primary keratinocytes showed significantly higher proliferation, greater ERK1/2 phosphorylation, and more active HRAS-GTP than wild-type cells; independently transfected HeLa cells showed increased ERK1/2 phosphorylation and active HRAS-GTP. The VCEP specifies that two or more different approved assays support Moderate strength. The exact variant has no pre-assigned code or matching row in the governing functional-studies table, so this application requires human review despite the assay-type match.
VCEP rule
Two or more different approved assays.
Evidence considered
SVI-RASopathy-VCEP-V2-Approved-Functional-Studies.xlsx, READ ME: RAS Activation Assay and ERK Activation Assay are approved pathway-specific assays, and two or more unique assay types for a variant provide sufficient evidence to upgrade PS3 to Moderate.
SVI-RASopathy-VCEP-V2-Approved-Functional-Studies.xlsx, RAS Activation Assay, HRAS column: approved assay; abnormal readout is increased RAS/RBD complexes compared with the positive-control range; proposed strength PS3_Supporting.
SVI-RASopathy-VCEP-V2-Approved-Functional-Studies.xlsx, ERK Activation Assay, HRAS column: approved assay; readout is pERK/ERK ratio and abnormal readout is constitutive, increased, or prolonged phosphorylation; proposed strength PS3_Supporting.
PMID:22683711, Functional characterization of the HRAS c.37G>C mutation: mutant primary keratinocytes showed higher proliferation, greater ERK1/2 phosphorylation, and more active HRAS-GTP than wild-type cells; transfected HeLa cells showed increased ERK1/2 phosphorylation and active HRAS-GTP.
PMID:22683711, Figure 4 legend: active HRAS-GTP was quantified by precipitation with Raf1-RBD agarose beads; ERK1/2 phosphorylation was measured by phosphorylation-specific immunoblotting, with n=3 for densitometric and HRAS activation analyses.
Still missing
No entry for c.37G>C, p.Gly13Arg, or p.G13R was found in SVI-RASopathy-VCEP-V2-Approved-Functional-Studies.xlsx after searching all three notations.
PM1ModerateVCEPMet at moderate: HRAS residue 13 falls within the VCEP-approved P-loop domain spanning amino acids 10-17.
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Reasoning
The variant changes HRAS residue 13. The HRAS VCEP v2.3 PM1 rule limits PM1 to the approved critical domains and lists the P-loop as amino acids 10-17, SW1 as 25-40, SW2 as 57-64, and SAK as 145-156. Residue 13 lies within the approved P-loop domain, so PM1 is met at Moderate strength. The governing Alignment-with-PM1-domains.pptx.pdf was also consulted; it contains the VCEP's PM1-domain alignment but no variant-specific row.
VCEP rule
Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).
Evidence considered
The HRAS VCEP v2.3 PM1 specification lists the approved P-loop domain as AA 10-17; residue 13 is inside this interval.
Alignment-with-PM1-domains.pptx.pdf was consulted as the PM1-specific VCEP file and provides the paralog alignment for the approved PM1 domains; no variant-specific row was present.
Still missing
No variant-specific entry for c.37G>C, p.Gly13Arg, or p.G13R was found in Alignment-with-PM1-domains.pptx.pdf; the domain rule independently maps residue 13 to P-loop 10-17.
PM2SupportingVCEPMet at Supporting: the variant is absent from both gnomAD v2.1 and v4.1, satisfying the VCEP's requirement for absence from gnomAD controls.
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Reasoning
The HRAS NM_005343.4:c.37G>C (p.Gly13Arg) variant was absent from the governing population-control sources gnomAD v2.1 and gnomAD v4.1. This satisfies the VCEP rule for PM2 at Supporting strength.
VCEP rule
The variant must be absent from controls (gnomAD).
Evidence considered
gnomAD v2.1 all-comers record for 11-534286-C-G: absent from controls.
gnomAD v4.1 all-comers record for chr11-534286-C-G: absent from controls.
PP3SupportingVCEPMet: REVEL score 0.791 meets the VCEP missense PP3 threshold of ≥0.7.
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Reasoning
The variant is a missense substitution, NM_005343.4:c.37G>C (NP_005334.1:p.(Gly13Arg)). The governing HRAS VCEP rule specifies REVEL ≥ 0.7 for missense variants. The recorded REVEL score is 0.791, so PP3 is met at Supporting strength. The separate splicing-impact clause is not needed for this missense path, and no other predictor is used.
VCEP rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
VCEP CSPEC PP3 rule: for missense variants, REVEL ≥ 0.7.
Local REVEL predictor lookup: NM_005343.4:c.37G>C, REVEL score 0.791; this exceeds the VCEP threshold of 0.7.
Variant normalization identifies NM_005343.4:c.37G>C as missense, NP_005334.1:p.(Gly13Arg).
BA1VCEPNot met: the variant is absent from gnomAD v2.1 and v4.1, so its filtering allele frequency is below the VCEP's 0.05% BA1 threshold.
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Reasoning
The HRAS NM_005343.4:c.37G>C (p.Gly13Arg) variant was absent from gnomAD v2.1 and gnomAD v4.1. Therefore, the VCEP's GnomAD filtering allele-frequency threshold of at least 0.05% is not reached.
VCEP rule
GnomAD filtering allele frequency ≥0.05%.
Evidence considered
gnomAD v2.1 all-comers record for 11-534286-C-G: absent; no allele frequency reported.
gnomAD v4.1 all-comers record for chr11-534286-C-G: absent; no allele frequency reported.
BS1VCEPNot met: the variant is absent from gnomAD v2.1 and v4.1, so its filtering allele frequency is below the VCEP's 0.025% BS1 threshold.
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Reasoning
The HRAS NM_005343.4:c.37G>C (p.Gly13Arg) variant was absent from gnomAD v2.1 and gnomAD v4.1. Therefore, the VCEP's GnomAD filtering allele-frequency threshold of at least 0.025% is not reached.
VCEP rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
gnomAD v2.1 all-comers record for 11-534286-C-G: absent; no allele frequency reported.
gnomAD v4.1 all-comers record for chr11-534286-C-G: absent; no allele frequency reported.
BP4VCEPNot met: REVEL score 0.791 exceeds the VCEP missense BP4 cutoff of ≤0.3.
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Reasoning
The variant is a missense substitution, NM_005343.4:c.37G>C (NP_005334.1:p.(Gly13Arg)), so the VCEP missense BP4 path applies. That path requires REVEL ≤ 0.3. The recorded REVEL score is 0.791, which is above the cutoff; therefore BP4 is not met. The available no-impact SpliceAI result is not used because the governing BP4 rule for this missense situation names REVEL only.
VCEP rule
For missense variants: REVEL ≤0.3.
Evidence considered
VCEP CSPEC BP4 rule: for missense variants, REVEL ≤ 0.3.
Local REVEL predictor lookup: NM_005343.4:c.37G>C, REVEL score 0.791; this exceeds the VCEP cutoff of 0.3.
Variant normalization identifies NM_005343.4:c.37G>C as missense, NP_005334.1:p.(Gly13Arg).
PS1VCEPNot assessed: reports document p.Gly13Arg from c.37G>C, but no independently established pathogenic p.Gly13Arg change from a different nucleotide was available.
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Reasoning
The HRAS p.Gly13Arg change is documented in PMID:22499344, PMID:22683711, and PMID:23884457, but these reports describe the queried c.37G>C nucleotide change itself. No evidence was found for a previously established pathogenic HRAS p.Gly13Arg variant produced by a different nucleotide change, which is required to apply the VCEP's PS1 rule. The governing VCEP alignment file was searched for c.37G>C, p.Gly13Arg, and p.G13R without a variant-specific entry.
VCEP rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in _HRAS, KRAS, MRAS, NRAS, RIT1,_ and _RRAS2._
Evidence considered
PMID:22499344 reports HRAS p.G13R (c.37G>C) in 21/24 HRAS-mutant keratinocytic epidermal nevi; this is the queried nucleotide change, not an alternate nucleotide producing the same amino-acid change.
PMID:22683711 reports HRAS c.37G>C resulting in p.Gly13Arg in 59/65 sebaceous nevi; this is the queried nucleotide change.
PMID:23884457 reports HRAS c.37G>C (p.Gly13Arg) in a Spitz-nevus case; this is the queried nucleotide change.
Alignment-with-PM1-domains.pptx.pdf was searched for c.37G>C, p.Gly13Arg, and p.G13R; no variant-specific entry was found.
Still missing
No alternate-nucleotide HRAS p.Gly13Arg/p.G13R pathogenic variant was identified.
No variant-specific entry for c.37G>C, p.Gly13Arg, or p.G13R was found in Alignment-with-PM1-domains.pptx.pdf.
PS2VCEPNot assessed: ClinVar labels two submissions de novo, but no proband phenotype, parental genotypes, or confirmed germline de novo event is documented.
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Reasoning
The HRAS VCEP provides PS2 point-based strengths, but the available evidence does not document an affected proband with confirmed parental testing, parental genotypes, or a countable de novo event. ClinVar contains two submissions labeled origin de novo, but provides no proband identity, phenotype, parental testing, or audit trail establishing that the queried variant was confirmed de novo. The variant-specific papers instead describe postzygotic somatic mosaicism in lesions and do not establish germline de novo status. Therefore PS2 cannot be assigned.
VCEP rule
4 Points. ... 2 Points. ... 1 Point.
Evidence considered
ClinVar variation 35554 lists two submissions with origin "de novo", but supplies no proband-level phenotype, parental genotypes, testing methodology, or auditable confirmation details for either submission.
PMID:22499344 reports HRAS c.37G>C in keratinocytic epidermal nevi and states that adjacent normal tissue and blood were wild type, supporting somatic lesion association rather than a documented germline de novo event.
PMID:22683711 reports HRAS c.37G>C in sebaceous nevi and describes detection in lesional but not tested nonlesional tissues, supporting postzygotic mosaicism; it does not report parental testing or germline de novo status.
Still missing
An auditable affected proband report for NM_005343.4:c.37G>C with phenotype details
Confirmed variant-negative parental genotypes and testing methodology
Evidence distinguishing germline de novo occurrence from postzygotic somatic mosaicism
PS4VCEPNot assessed: lesion cohorts report 21/24 and 59/65 variant-positive lesions, but provide no affected-versus-control case-control counts for OR/95% CI calculation.
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Reasoning
The HRAS c.37G>C (p.Gly13Arg) literature includes variant-positive somatic lesion cohorts, including 21/24 HRAS-mutant keratinocytic epidermal nevi and 59/65 sebaceous nevi, but these are not case-control comparisons of affected patients versus unaffected or population controls. Adjacent normal tissue is a tissue-level mosaicism comparison, not an unaffected control cohort, so an OR and 95% CI cannot be computed from the available counts. The VCEP also permits a moderate alternative for multiple unrelated patients with the same phenotype and absence in controls, but the available reports do not establish the required number of unrelated RASopathy probands with comparable phenotype; the cohorts are principally somatic mosaic nevi. The governing PS4 strength operators are >=5 points, >=3 points, and >=1 point, but no defensible PS4 point total is available; therefore the criterion is not assessed.
VCEP rule
Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)). ... The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. ... Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. ... ≥5 points. ... ≥3 points. ... ≥1 point.
Evidence considered
VCEP PS4: point-based scoring for autosomal dominant cases with phenotypic specifications; the available variant-positive reports are somatic mosaic lesion studies rather than qualifying germline RASopathy case-control cohorts.
Hafner et al. 2012, PMID:22499344, Results/Table 1: HRAS p.G13R (c.37G>C) occurred in 21/24 HRAS-mutant keratinocytic epidermal nevi; adjacent normal tissue and blood were wild type in tested cases, but no unaffected control cohort was reported.
Groesser et al. 2012, PMID:22683711, Abstract/Results/Table 1: HRAS c.37G>C occurred in 59/65 sebaceous nevi; nonlesional tissues were tested in 18 individuals, but no independent control cohort or case-control counts were given.
Sarin et al. 2013, PMID:23884457, Results/Figure 2: HRAS c.37G>C was detected in four Spitz nevi from one patient and absent from adjacent normal skin; this is not a case-control study.
gnomAD v2.1 and v4.1 report the variant absent, but no affected-patient frequency and matched-ancestry control frequency are available, so no OR or 95% CI was computed.
Still missing
A qualifying case-control study with affected-patient and unaffected or matched-ancestry control counts is unavailable.
The available papers do not establish a qualifying count of unrelated RASopathy probands with the same phenotype for the VCEP alternative path.
A defensible VCEP PS4 point total cannot be assigned.
PM5VCEPNot assessed: the candidate search found zero alternate-residue candidates at codon 13, so neither the one-change nor two-change PM5 threshold was established.
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Reasoning
The VCEP requires one likely pathogenic residue change at the same codon for PM5 at Moderate strength, or at least two different likely pathogenic residue changes at the same codon observed in at least five probands for Strong strength. The available PM5 candidate collection found zero same-residue candidates, and the reviewed exact-variant papers report p.Gly13Arg from c.37G>C rather than alternate amino-acid changes at codon 13. Therefore the available evidence does not permit PM5 assessment.
VCEP rule
≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands. ... 1 [likely] pathogenic residue change at the same codon.
Evidence considered
pm5_candidates.json reports zero same-residue candidates, zero expert-panel likely pathogenic candidates, and zero non-expert-majority likely pathogenic candidates.
PMID:22499344, PMID:22683711, and PMID:23884457 report the queried p.Gly13Arg/c.37G>C variant, not alternate amino-acid changes at codon 13.
Alignment-with-PM1-domains.pptx.pdf was searched for c.37G>C, p.Gly13Arg, and p.G13R; no variant-specific entry was found.
Still missing
No likely pathogenic alternate amino-acid change at HRAS codon 13 was identified.
No variant-specific entry for c.37G>C, p.Gly13Arg, or p.G13R was found in Alignment-with-PM1-domains.pptx.pdf.
PM6VCEPNot assessed: Two ClinVar submissions are labeled de novo, but parental testing and a countable unconfirmed germline de novo observation are absent.
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Reasoning
The HRAS VCEP provides PM6 point-based strengths for an assumed de novo occurrence, but the available evidence does not establish a proband-level de novo variant without confirmed parental testing or provide a countable point assignment. ClinVar labels two submissions origin de novo without parental genotype details, and the variant-specific papers describe somatic mosaicism rather than an unconfirmed germline de novo event. Therefore PM6 cannot be assigned.
VCEP rule
2 Points. ... 1 Point. ... 0.5 Points.
Evidence considered
ClinVar variation 35554 lists two submissions with origin "de novo", but provides no proband phenotype, parental testing results, or evidence sufficient to classify the event as an unconfirmed germline de novo occurrence.
PMID:22499344 describes lesion-restricted HRAS c.37G>C with wild-type adjacent tissue and blood in tested cases, not parental testing or an unconfirmed germline de novo observation.
PMID:22683711 describes HRAS c.37G>C in lesional keratinocytes with postzygotic mosaicism and does not provide parental testing or a PM6-eligible germline observation.
Still missing
An auditable affected proband report for NM_005343.4:c.37G>C
Documented absence or incomplete testing of both biological parents
Evidence that the observation is germline rather than postzygotic somatic mosaicism
PP1VCEPNot assessed: No pedigree, relative genotypes, or informative meioses are reported, so the VCEP's minimum 3-meiosis PP1 threshold cannot be evaluated.
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Reasoning
No affected relatives, unaffected relatives, pedigree, parental segregation results, or informative meioses are documented for NM_005343.4:c.37G>C. The available variant-specific papers concern somatic mosaic lesions and do not provide familial segregation. Because the HRAS VCEP assigns PP1 solely by the number of informative meioses, no PP1 strength can be assigned.
The case evidence contains no pedigree, familial genotype results, affected-relative observations, or informative-meiosis count for NM_005343.4:c.37G>C.
PMID:22499344 is a somatic keratinocytic epidermal-nevus cohort and reports lesion-associated mutation testing, not familial segregation.
PMID:22683711 is a somatic sebaceous-nevus study describing postzygotic mosaicism, not familial segregation.
BS2VCEPNot assessed: no unaffected-individual or homozygote observations are available to assign the VCEP's -4-point or -1-point BS2 outcome.
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Reasoning
The VCEP defines BS2 using point values, but the available evidence does not report unaffected individuals, homozygotes, or the observations needed to assign either the -4-point or -1-point outcome. The criterion cannot be evaluated.
VCEP rule
-4 Points; -1 Point.
Evidence considered
No BS2-specific unaffected-individual, homozygote, or point-count evidence was reported in the case evidence.
Still missing
Unaffected individual and homozygote observation data sufficient to assign the VCEP's BS2 point value.
BS4VCEPNot assessed: No affected variant-negative relative or informative non-segregating meiosis is documented against the VCEP's one-meiosis BS4 requirement.
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Reasoning
No affected relative documented to lack NM_005343.4:c.37G>C, no pedigree, no genotype-phenotype discordance, and no informative non-segregating meiosis are available. The variant-specific papers report somatic mosaicism in lesions rather than familial non-segregation. The HRAS VCEP requires one informative meiosis for BS4, but none is documented; therefore BS4 cannot be assigned.
VCEP rule
Requires only one informative meiosis.
Evidence considered
The case evidence contains no affected relative who is negative for NM_005343.4:c.37G>C, no pedigree, and no informative non-segregating meiosis.
PMID:22499344 reports wild-type adjacent tissue and blood in a somatic lesion study; these are not affected relatives and do not constitute familial non-segregation.
PMID:22683711 reports postzygotic mosaicism in lesional versus nonlesional tissues and provides no familial genotype-phenotype non-segregation analysis.
Still missing
Auditable pedigree and phenotype information
Genotype results from affected relatives who lack the variant
BP2VCEPNot assessed: no VCEP-defined BP2 point assignment or documented cis/trans phase observation is available to reach the ≥(-1)-point supporting threshold.
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Reasoning
The HRAS VCEP specifies BP2 only through strength thresholds expressed as negative points: Strong at ≥ (-4) Points, Moderate at ≥ (-2) Points, and Supporting at ≥ (-1) Point. The available evidence reports this variant in postzygotic mosaic lesions and does not provide a VCEP-defined point assignment for a pathogenic variant in cis or trans, phase, or an affected-proband allelic observation. Because the governing point score cannot be evaluated from the available evidence, BP2 is not assessed.
The available variant-specific publications describe postzygotic mosaic HRAS c.37G>C/p.Gly13Arg in somatic lesions, not a documented VCEP-scored cis/trans occurrence with a pathogenic allele in an affected proband.
Still missing
A VCEP-defined BP2 point assignment based on documented cis/trans phase and an allelic pathogenic-variant observation is unavailable.
BP5VCEPNot assessed: no documented alternative molecular diagnosis or BP5 point total is available to evaluate the VCEP's >=(-1), >=(-2), or >=(-4) thresholds.
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Reasoning
BP5 is applicable under the HRAS VCEP when an alternative molecular cause of a RASopathy in a different gene is present with a consistent phenotype, or when an inconsistent phenotype is fully explained by a different causative variant. The available case evidence contains no documented alternative causative variant, no qualifying different-gene molecular diagnosis, and no point assignment. The VCEP operators are >=(-4) points for Strong, >=(-2) points for Moderate, and >=(-1) point for Supporting; because no BP5 points are available, no substituted inequality can be evaluated and the criterion is not assessed.
VCEP rule
Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing). ... ≥ (-4) Points. ... ≥ (-2) Points. ... ≥ (-1) Point.
Evidence considered
HRAS VCEP BP5 instructions require an alternative molecular cause in a different gene with phenotype consistency, or an inconsistent phenotype fully explained by another causative variant; no such evidence is documented.
VCEP BP5 thresholds are >=(-4) Points for Strong, >=(-2) Points for Moderate, and >=(-1) Point for Supporting; no point value is available for substitution into an inequality.
Still missing
A documented alternative molecular cause in a different gene or a fully explanatory different causative variant is unavailable.
The VCEP BP5 point score cannot be assigned from the available case evidence.
Not applicable · 11· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1VCEPNot applicable: the VCEP explicitly marks PVS1 not applicable, and this variant is missense p.(Gly13Arg), not a loss-of-function change.
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Reasoning
The HRAS VCEP specification explicitly marks PVS1 as not applicable. The queried variant is NM_005343.4:c.37G>C, a missense variant producing NP_005334.1:p.(Gly13Arg) in exon 2 rather than a loss-of-function consequence; therefore no PVS1 strength tier is assigned.
Variant-level assessment: NM_005343.4:c.37G>C produces NP_005334.1:p.(Gly13Arg), is classified as missense, and is in exon 2; it is not a truncating, splice-consensus, or other loss-of-function variant.
PM3VCEPNot applicable: the HRAS VCEP explicitly marks PM3 as not applicable, regardless of the reported mosaic lesion observations.
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Reasoning
The HRAS VCEP specification explicitly marks PM3 as Not Applicable. Therefore, reported observations of HRAS c.37G>C/p.Gly13Arg in mosaic somatic lesions, without germline phase or affected-proband trans observations, cannot activate PM3 under this VCEP framework.
VCEP rule
Not Applicable
Evidence considered
ClinGen RASopathy Expert Panel HRAS v2.3 CSPEC entry for PM3: applicability is explicitly recorded as Not Applicable.
Available variant reports concern postzygotic mosaic somatic lesions rather than documented germline affected-proband phase or trans observations, but this does not alter the VCEP's explicit PM3 applicability designation.
PM4N/ANot applicable: p.(Gly13Arg) is a missense substitution with no protein-length change, and PM4 addresses protein-length changes outside repetitive regions.
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Reasoning
The VCEP PM4 entry states, "No known repetitive areas in gene. Use as described." This variant is a missense substitution, NM_005343.4:c.37G>C, p.(Gly13Arg), with no protein-length change; it therefore does not fall within the protein-length-change scope of PM4.
VCEP rule
No known repetitive areas in gene. Use as described.
Evidence considered
ClinGen RASopathy Expert Panel HRAS specification v2.3 PM4 entry: "No known repetitive areas in gene. Use as described."
Variant-level assessment: NM_005343.4:c.37G>C is a missense substitution producing p.(Gly13Arg), with no insertion, deletion, stop-loss, or other protein-length change.
PP5VCEPNot applicable: the HRAS VCEP prohibits PP5 use regardless of the available ClinVar pathogenic assertions.
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Reasoning
The HRAS VCEP marks PP5 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ClinVar classifications and publication assertions therefore do not support applying PP5 here.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
HRAS VCEP CSPEC PP5 entry: the criterion is not for use; ClinVar reports Pathogenic/Likely pathogenic submissions but cannot override the VCEP applicability rule.
BS3VCEPNot applicable: the HRAS VCEP Version 2.3 explicitly marks BS3 as not applicable for this framework.
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Reasoning
BS3 is not applicable under the HRAS VCEP Version 2.3 specification. The VCEP explicitly marks BS3 as not applicable, regardless of whether functional evidence is available; therefore no benign functional evidence is assigned under this criterion.
VCEP rule
Not applicable
Evidence considered
ClinGen RASopathy Expert Panel Specifications for HRAS Version 2.3, BS3 criterion entry: applicability is Not applicable.
BP1N/ANot applicable: p.Gly13Arg is missense, whereas the VCEP BP1 rule is restricted to truncating variant types.
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Reasoning
The queried variant is a missense variant, p.Gly13Arg. The HRAS VCEP BP1 rule applies to truncating variants including nonsense, frameshift, canonical splice-site, initiation-codon, whole-gene, or multi-exon deletion variants in genes without established loss-of-function correlation; none of those variant types describes this missense change.
VCEP rule
This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.
Evidence considered
The case normalization identifies NP_005334.1:p.(Gly13Arg), a missense variant.
The HRAS VCEP BP1 rule names truncating variants and does not include missense variants.
BP3VCEPNot applicable: the VCEP explicitly marks BP3 not applicable, and this variant is missense rather than an in-frame indel in a repetitive region.
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Reasoning
The HRAS VCEP specification explicitly marks BP3 as not applicable. The variant is a missense substitution, not an in-frame deletion or insertion in a repetitive region, so BP3 cannot be applied under this VCEP framework.
BP6VCEPNot applicable: the HRAS VCEP prohibits BP6 use regardless of any reputable-source benign assertion.
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Reasoning
The HRAS VCEP marks BP6 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
HRAS VCEP CSPEC BP6 entry: the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7N/ANot applicable: the variant is missense, whereas VCEP BP7 covers synonymous, noncanonical intronic, and non-coding variants.
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Reasoning
The variant is missense, NM_005343.4:c.37G>C (NP_005334.1:p.(Gly13Arg)). The governing VCEP BP7 rule applies to synonymous variants and also to intronic positions except canonical splice sites or non-coding variants. A missense variant is outside that scope, so BP7 is not_applicable without evaluating splice prediction or nucleotide conservation.
VCEP rule
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.
Evidence considered
VCEP CSPEC BP7 rule limits the criterion to synonymous variants, noncanonical intronic positions, or non-coding variants.
Variant normalization identifies NM_005343.4:c.37G>C as a missense variant producing NP_005334.1:p.(Gly13Arg).
Every interpreted variant in HRAS, mapped onto the exon structure of NM_005343.4. Select a row to find it on the plot.
HRASNM_005343.4
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—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat +68 bp
0.000
SpliceAI acceptor gainat +80 bp
0.005
SpliceAI donor lossat -263 bp
0.002
SpliceAI donor gainat +426 bp
0.003
Pangolin splice lossmagnitude shown
-0.003
Pangolin splice gain
0.005
Other predictors
REVEL
0.791
BayesDel
0.274
How the predictions were used
PP3SupportingVCEPMet: REVEL score 0.791 meets the VCEP missense PP3 threshold of ≥0.7.
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Reasoning
The variant is a missense substitution, NM_005343.4:c.37G>C (NP_005334.1:p.(Gly13Arg)). The governing HRAS VCEP rule specifies REVEL ≥ 0.7 for missense variants. The recorded REVEL score is 0.791, so PP3 is met at Supporting strength. The separate splicing-impact clause is not needed for this missense path, and no other predictor is used.
VCEP rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
VCEP CSPEC PP3 rule: for missense variants, REVEL ≥ 0.7.
Local REVEL predictor lookup: NM_005343.4:c.37G>C, REVEL score 0.791; this exceeds the VCEP threshold of 0.7.
Variant normalization identifies NM_005343.4:c.37G>C as missense, NP_005334.1:p.(Gly13Arg).
BP4VCEPNot met: REVEL score 0.791 exceeds the VCEP missense BP4 cutoff of ≤0.3.
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Reasoning
The variant is a missense substitution, NM_005343.4:c.37G>C (NP_005334.1:p.(Gly13Arg)), so the VCEP missense BP4 path applies. That path requires REVEL ≤ 0.3. The recorded REVEL score is 0.791, which is above the cutoff; therefore BP4 is not met. The available no-impact SpliceAI result is not used because the governing BP4 rule for this missense situation names REVEL only.
VCEP rule
For missense variants: REVEL ≤0.3.
Evidence considered
VCEP CSPEC BP4 rule: for missense variants, REVEL ≤ 0.3.
Local REVEL predictor lookup: NM_005343.4:c.37G>C, REVEL score 0.791; this exceeds the VCEP cutoff of 0.3.
Variant normalization identifies NM_005343.4:c.37G>C as missense, NP_005334.1:p.(Gly13Arg).
BP7N/ANot applicable: the variant is missense, whereas VCEP BP7 covers synonymous, noncanonical intronic, and non-coding variants.
Details ▾Hide ▴
Reasoning
The variant is missense, NM_005343.4:c.37G>C (NP_005334.1:p.(Gly13Arg)). The governing VCEP BP7 rule applies to synonymous variants and also to intronic positions except canonical splice sites or non-coding variants. A missense variant is outside that scope, so BP7 is not_applicable without evaluating splice prediction or nucleotide conservation.
VCEP rule
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.
Evidence considered
VCEP CSPEC BP7 rule limits the criterion to synonymous variants, noncanonical intronic positions, or non-coding variants.
Variant normalization identifies NM_005343.4:c.37G>C as a missense variant producing NP_005334.1:p.(Gly13Arg).
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.791. BayesDel score = 0.274161.
8 paper records listed. 1 cited in the classification.
Cited in the classification
Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.
Groesser L et al. · 2012 Jun 10
The paper reports HRAS c.37G>C producing p.Gly13Arg in 59 of 65 sebaceous nevi and describes functional activation in mutant keratinocytes; the reported nucleotide change is the queried change.
Conformational states of human rat sarcoma (Ras) protein complexed with its natural ligand GTP and their role for effector interaction and GTP hydrolysis.
Recurrent reciprocal translocations and insertions that form chimeric fusion genes.
Sections 1.3 and 1.5, Mutational spectrum
Keratinocytic epidermal nevi are associated with mosaic RAS mutations.
Hafner C et al. · 2012
The paper reports HRAS p.G13R (c.37G>C) in 21 of 24 HRAS-mutant keratinocytic epidermal nevi and describes it as a recurrent hotspot mutation; the reported nucleotide change is the queried change.
Comparison of recurrent variants from the exome sequencing identified an HRAS point mutation (c.37G→C, p.Gly13Arg) in both Spitz nevi that was absent in the adjacent normal skin.
Results section; Figure 2A-B and 2G
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (7 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 35554)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.791. BayesDel score = 0.274161.
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 lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54236651, n = 466 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.