HRAS

Final classification

VUS

HRAS c.37_39delinsAAA · p.Gly13Lys

HRAS

NM_005343.4:c.37_39delinsAAA (p.Gly13Lys) is an in-frame indel in HRAS exon 2 that substitutes Gly13 with Lys within the highly conserved P-loop GTP-binding domain (residues 10–17).

Gene

HRAS

Transcript

NM_005343.4

HGVS · transcript:coding

NM_005343.4:c.37_39delinsAAA

Consequence

N/A

GRCh38

chr11:534284 ACC>TTT

GRCh37

chr11:534284 ACC>TTT

Basis ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, PP2 supporting; combination = 2 moderate + 1 supporting, which maps to VUS. ▾

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, PP2 supporting; combination = 2 moderate + 1 supporting, which maps to VUS.

Classification rationale

PM1PM2PP2 VUS

HRAS c.37_39delinsAAA

NM_005343.4:c.37_39delinsAAA (p.Gly13Lys) is an in-frame indel in HRAS exon 2 that substitutes Gly13 with Lys within the highly conserved P-loop GTP-binding domain (residues 10–17).¹ This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.² Gly13 lies in the P-loop, a critical functional domain for GTP binding, which is an approved mutational hotspot domain per the RASopathy VCEP.³ The ClinGen RASopathy VCEP designates PP2 as applicable to all RASopathy genes; HRAS has a low rate of benign missense variation and missense variants are the primary disease mechanism.⁴ No functional studies have directly tested G13K. The VCEP-approved RAS Activation Assay for HRAS validated G13C and G13D as pathogenic but did not include G13K.⁵ PVS1, PP4, PP5, and BP6 are designated as Not Applicable by the RASopathy VCEP. PS5 is not defined in the VCEP criteria.⁶ Based on PM1 (Moderate), PM2 (Moderate), and PP2 (Supporting), this variant meets criteria for Likely Pathogenic under the ACMG/AMP 2015 scoring framework.⁷

PM1 + PM2 + PP2 → VUS

1 cspec ↗vcep_alignment_with_pm1_domains_pptx

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 vcep_alignment_with_pm1_domains_pptxcspec ↗

4 cspec ↗

5 vcep_svi_rasopathy_vcep_v2_approved_functional_studies

6 cspec ↗

7 cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗vcep_alignment_with_pm1_domains_pptx

Gene diagram · NM_005343.4 · variants mapped to exon structure

HRAS NM_005343.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 18 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PM1 moderate Pathogenic

The variant results in Gly13Lys, located within the P-loop (HRAS residues 10–17), an approved mutational hotspot and critical functional domain per the RASopathy VCEP supplemental material. The P-loop is essential for GTP binding, and this residue is a statistically significant hotspot in cancerhotspots.org.

P-loop domain (HRAS 10–17) is an approved VCEP PM1 domainGly13 lies within this domain.Statistically significant hotspot at this residue per cancerhotspots.org.

cspec ↗

✓

PM2 moderate Pathogenic

The variant is completely absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, satisfying the VCEP requirement for complete absence from all population databases.

Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).Absent from gnomAD-Canada v1.0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP2 supporting Pathogenic

The RASopathy VCEP states that PP2 is applicable to all RASopathy genes described and curated in the specification. HRAS is a curated RASopathy gene with a low rate of benign missense variation, and missense variants are the primary mechanism of disease (gain-of-function). Although this variant is an indel, it produces a single amino acid substitution (Gly13Lys) consistent with missense-like behavior.

VCEP: PP2 is applicable to all RASopathy genes.HRAS has a low rate of benign missense variationmissense is the primary disease mechanism.

cspec ↗

Assessed · not applied

Pathogenic

PS1 No previously established pathogenic variant resulting in the same amino acid change (Gly13Lys) from a different nucleotide change has been identified.

PS2 No de novo occurrence data are available for this variant.

PS3 The VCEP-approved RAS Activation Assay for HRAS is validated for G13C and G13D (both pathogenic), but G13K was not directly tested in any approved functional study.

PS4 No independent proband occurrences have been identified.

PM4 PM4 requires protein length changes due to in-frame deletions/insertions or stop-loss variants.

PM6 No de novo occurrence data, confirmed or assumed, are available for this variant.

PP1 No co-segregation data are available.

PP3 Computational prediction tools (REVEL, BayesDel) are not applicable to this indel variant.

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 The VCEP-approved functional studies for HRAS did not test G13K directly.

BS4 No segregation data are available to evaluate lack of segregation in affected family members.

BP1 BP1 applies to truncating variants (nonsense, frameshift, canonical splice site, initiation codon, multi-exon deletion) in genes without established LOF correlation.

BP2 No evidence of the variant occurring in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant.

BP3 BP3 requires an in-frame deletion/insertion in a repetitive region without known function.

BP4 No computational evidence suggests no impact on the gene product.

BP5 No evidence of an alternate molecular basis for disease has been identified in cases carrying this variant.

N/A · 6 PVS1 · PM5 · PP4 · PP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

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

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 is absent from ClinVar.

ClinVar ↗

In silico No data

No in-silico prediction was recorded for this variant.

SpliceAI ↗

Functional Likely Oncogenic

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 Hotspot

COSMIC

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

Hotspots

This variant lies 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