Classification rationale

PP2 VUS

HRAS c.374T>C

PP2 was applied at supporting strength per RASopathy VCEP specification, as PP2 is applicable to all RASopathy genes curated by this expert panel.¹ The variant p.Val125Ala is present in gnomAD v4.1 at extremely low frequency (2/1,613,828 alleles; AF = 1.24e-6), precluding PM2 (requires complete absence per VCEP) but remaining far below BA1 (>=0.05%) and BS1 (>=0.025%) thresholds.² No functional studies have characterized p.Val125Ala in any VCEP-approved assay; PS3 and BS3 cannot be applied.³ The variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories, ClinVar ID 981547) with criteria provided by a single submitter. No expert panel review has been performed.⁴

PP2 → VUS

1 cspec ↗

2 gnomad_v4 ↗

3 vcep_svi_rasopathy_vcep_v2_approved_functional_studiesoncokb ↗

4 clinvar ↗

Gene diagram · NM_001130442.2 · variants mapped to exon structure

HRAS NM_001130442.2

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 18 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PP2 supporting Pathogenic

The RASopathy VCEP specifies PP2 as applicable to all RASopathy genes curated in the specification. HRAS is a RASopathy gene, and this is a missense variant (p.Val125Ala). Per VCEP: 'PP2 is applicable to all RASopathy genes described and curated herein.'

RASopathy VCEP: PP2 applicable to all curated RASopathy genes including HRASVariant is missense in a gene where missense variants are a common mechanism of disease

cspec ↗

Assessed · not applied

Pathogenic

PS1 No previously established pathogenic variant with the same amino acid change (p.Val125Ala) has been identified in HRAS.

PS2 No de novo occurrence with confirmed paternity has been reported in the literature for this variant.

PS3 The RASopathy VCEP-approved functional studies (RAS Activation Assay, MEK Activation Assay, ERK Activation Assay) have been validated for HRAS, but the specific variant p.Val125Ala (V125A) is not among the validation controls tested in any approved study.

PS4 No independent occurrences meeting the VCEP threshold have been identified.

PM1 Position 125 is not located within a VCEP-approved PM1 functional domain.

PM2 The RASopathy VCEP requires complete absence from all population databases for PM2 application.

PM5 No pathogenic missense variant at the same amino acid residue (position 125) has been identified in HRAS.

PM6 No assumed or confirmed de novo occurrence has been reported in the literature for this variant.

PP1 No co-segregation data are available.

PP3 The VCEP requires multiple lines of computational evidence supporting a deleterious effect.

Benign

BA1 The VCEP BA1 threshold is allele frequency >= 0.05%.

BS1 The VCEP BS1 threshold is allele frequency >= 0.025%.

BS2 The VCEP specifies that general population data should not be used for BS2 due to variable expressivity and severity of RASopathies.

BS3 No VCEP-approved functional studies have been performed for this variant.

BS4 The VCEP requires one informative meiosis demonstrating lack of segregation.

BP2 No evidence that this variant has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern.

BP4 The VCEP requires multiple lines of computational evidence suggesting no impact on gene or gene product.

BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease.

N/A · 6 PVS1 · PP4 · PP5 · BP1 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23929e-06; MAF= 0.00012%, 2/1613828 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69496e-06; MAF= 0.00017%, 2/1179970 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,613,828
0 hom · FAF 2.8e-05%

European (non-Finnish)

2 / 1,179,970

0.00017%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 981547)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.879. BayesDel score = 0.121936.

SpliceAI ↗

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 4 PMIDs not cited in assessment

20301303 ↗ Noonan Syndrome. CLINVAR

20301680 ↗ HRAS-Related Costello Syndrome. CLINVAR

20876176 ↗ Noonan syndrome: clinical features, diagnosis, and management guidelines. CLINVAR

25173338 ↗ 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). CLINVAR