Variant classification summary

NM_005343.4:c.182A>G

HRAS · NP_005334.1:p.(Gln61Arg) · NM_005343.4

GRCh37: chr11:533874 T>C · GRCh38: chr11:533874 T>C

Gene: HRAS Transcript: NM_005343.4

Final call

Pathogenic

PS1 strong PM1 moderate PM2 supporting PM5 moderate PP3 supporting

Variant details

Gene

HRAS

Transcript

NM_005343.4

Protein

NP_005334.1:p.(Gln61Arg)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The c.182A>G (p.Gln61Arg) missense variant in HRAS is classified as Pathogenic under the ClinGen RASopathy VCEP v2.3.0 framework.

2

PS1 (Strong): p.Gln61Arg is a previously established pathogenic variant at the analogous residue in KRAS and NRAS, satisfying the VCEP rule for cross-gene analogous residue application.

3

PM1 (Moderate): The variant falls within the Switch II domain (SW2, AA 57-64), a VCEP-defined critical functional domain essential for GTP hydrolysis and GAP interaction. Residue Q61 is a statistically significant cancer hotspot (cancerhotspots.org) with 417 somatic occurrences in COSMIC.

4

PM5 (Moderate): At least one other pathogenic missense change at codon 61 (e.g., Q61L) has been established in HRAS, meeting the VCEP threshold for PM5 at Moderate strength.

5

PM2 (Supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting the VCEP requirement for absence from controls.

6

PP3 (Supporting): The REVEL score of 0.811 exceeds the VCEP threshold of >=0.7 for pathogenic computational prediction. SpliceAI predicts no splice impact (max delta = 0.00).

7

Combination: PS1 (1 Strong) + PM1 (1 Moderate) + PM5 (1 Moderate) + PM2 (1 Supporting) + PP3 (1 Supporting) satisfies VCEP Rule 7 (1 Strong + 2 Moderate + >=2 Supporting = Pathogenic).

Final determination: Rule7 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is not applicable per the ClinGen RASopathy VCEP v2.3.0 for HRAS. This is a missense variant (p.Gln61Arg), not a null variant (nonsense, frameshift, or canonical splice variant).	cspec
PS1	Met	The p.Gln61Arg substitution is a previously established pathogenic variant at the analogous residue in KRAS and NRAS. Per the RASopathy VCEP, PS1 is applicable for observed analogous residue positions across HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2. Q61R in KRAS and NRAS is a well-established oncogenic gain-of-function mutation catalogued in COSMIC and ClinVar.	cspec oncokb
PS2	Not met	No de novo occurrence data are available for this variant. PS2 requires confirmed de novo status (both maternity and paternity confirmed) in a patient with a RASopathy phenotype and no family history.
PS3	Not assessed	Primary functional study publications for HRAS Q61R were not available for full-text review in the case folder. OncoKB curates HRAS Q61R as Likely Oncogenic/Likely Gain-of-function, and the structural biology literature (PMID:9219684) establishes that Gln61 is essential for GAP-mediated GTP hydrolysis — its mutation constitutively activates Ras. However, variant-specific functional data from VCEP-approved assays (RAS Activation, MEK Activation, ERK Activation) could not be verified from primary sources.	oncokb PMID:9219684
PS4	Not met	No proband count data are available to meet the VCEP point-based scoring threshold. While this variant is reported in ClinVar (VCV000160364) as Likely pathogenic/Pathogenic by clinical laboratories and has been observed in somatic cancers (COSMIC, n=417), specific proband counts with RASopathy phenotypes are not available for PS4 point calculation.	clinvar
PS5	N/A	PS5 was not included in the adjudication list for this case.
PM1	Met	The variant substitutes Gln61Arg within the Switch II (SW2) domain (HRAS amino acids 57-64), a critical and well-established functional domain defined by the RASopathy VCEP. SW2 is essential for GTP hydrolysis and GAP interaction. Residue Q61 is a known cancer hotspot (cancerhotspots.org) and is recurrently mutated in somatic cancers (COSMIC n=417). No benign variation is observed at this residue.	cspec PMID:9219684
PM2	Met	The variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the VCEP requirement for absence from population controls.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 is not applicable per the RASopathy VCEP; HRAS-related RASopathies are autosomal dominant disorders, not recessive.	cspec
PM4	N/A	PM4 applies to in-frame deletions/insertions and stop-loss variants causing protein length changes. This is a missense substitution.
PM5	Met	At least one other pathogenic missense change has been established at codon 61 of HRAS. The RASopathy VCEP recognizes Q61L (c.182A>T) and Q61K as pathogenic/likely pathogenic changes at the same codon, satisfying the requirement for one (likely) pathogenic residue change at the same codon.	cspec clinvar
PM6	Not met	No assumed de novo data are available for this variant. PM6 requires observation of the variant as assumed de novo (without confirmation of both maternity and paternity) in a patient with a RASopathy phenotype.
PP1	Not met	No co-segregation data are available for this variant. PP1 requires observation of the variant in affected family members (≥3 informative meioses for Supporting, ≥5 for Moderate, ≥7 for Strong).
PP2	N/A	PP2 is not applicable per the RASopathy VCEP because the missense z-score for HRAS is <3.09 in gnomAD.	cspec
PP3	Met	REVEL score of 0.811 meets the VCEP threshold of ≥0.7 for pathogenic computational evidence. SpliceAI predicts no splice impact (max delta score = 0.00), consistent with a missense effect rather than a splicing defect. The disease mechanism (gain-of-function) is consistent with a missense change.	revel spliceai cspec
PP4	N/A	PP4 is not applicable per the RASopathy VCEP; phenotype specificity is assessed under PS4.	cspec
PP5	N/A	PP5 is not for use per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation for this VCEP.	cspec
BA1	Not met	The variant is absent from gnomAD (filtering allele frequency = 0), which is far below the VCEP stand-alone benign threshold of ≥0.05%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD (filtering allele frequency = 0), which is below the VCEP strong benign threshold of ≥0.025%.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available documenting this variant in healthy adult individuals. BS2 requires observation in a healthy adult for a dominant disorder with full penetrance expected at an early age.
BS3	N/A	BS3 is not applicable per the RASopathy VCEP for HRAS.	cspec
BS4	Not met	No segregation data demonstrating lack of co-segregation with disease are available. BS4 requires at least one informative meiosis showing the variant does not segregate with the RASopathy phenotype.
BP1	N/A	BP1 per the RASopathy VCEP is specifically for truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, gene deletions) in RASopathy genes where the disease mechanism is gain-of-function. This is a missense variant; BP1 does not apply.	cspec
BP2	Not met	No evidence of an alternative molecular cause for a RASopathy in HRAS (in cis/trans with another pathogenic variant) is available. BP2 requires point-based scoring from alternative molecular diagnoses.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
BP4	Not met	REVEL score of 0.811 exceeds the VCEP benign threshold of ≤0.3. Multiple lines of computational evidence support a deleterious effect (REVEL 0.811, BayesDel 0.249), contradicting BP4 application.	revel bayesdel
BP5	Not met	No evidence of an alternative molecular basis for disease in a different gene is available. BP5 requires point-based scoring for an alternative molecular cause of a RASopathy.
BP6	N/A	BP6 is not for use per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation for this VCEP.	cspec
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a missense variant (p.Gln61Arg).

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