Variant classification summary

NM_005343.4:c.7G>A

HRAS · NP_005334.1:p.(Glu3Lys) · NM_005343.4

GRCh37: chr11:534316 C>T · GRCh38: chr11:534316 C>T

Gene: HRAS Transcript: NM_005343.4

Final call

VUS

PM2 supporting

Variant details

Gene

HRAS

Transcript

NM_005343.4

Protein

NP_005334.1:p.(Glu3Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

2

With only this Supporting criterion met, no combination rule fires and the variant is classified as a variant of uncertain significance (VUS).

Final determination: No criteria-combination rule in the ClinGen RASopathy Expert Panel HRAS Version 2.3 cspec_ruleset is satisfied by PM2 (Supporting) alone, so the variant is classified as Variant of Uncertain Significance.

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	Not applicable: missense substitution with no reading-frame, splice-site, or start-codon disruption, so no loss-of-function mechanism applies.	cspec
PS1	Not assessed	Not assessed: no pathogenic same-amino-acid comparator was found in HRAS; the paralog-gene comparison was not performed.	cspec pm5_candidates clinvar
PS2	Not assessed	Not assessed: no proband-level de novo observation with parental testing or family history was available.	cspec
PS3	Not assessed	Not assessed: no functional assay data for p.(Glu3Lys) from a VCEP-approved assay type was identified.	oncokb
PS4	Not assessed	Not assessed: no case-control enrichment data or affected-case counts were available for scoring.	cspec
PM1	Not met	Not met: codon 3 falls outside all four VCEP critical domains (P-loop, Switch I, Switch II, SAK).	cspec
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the HRAS VCEP v2.3 specification excludes this criterion.	cspec
PM4	N/A	Not applicable: single amino-acid substitution with no protein length change, so no in-frame indel or stop-loss to assess.	cspec
PM5	Not met	Not met: no established pathogenic amino acid change at codon 3 was found in ClinVar.	pm5_candidates cspec
PM6	Not assessed	Not assessed: no proband observation or parental genotypes establishing an assumed de novo event were available.	cspec
PP1	Not assessed	Not assessed: no affected or unaffected relatives or informative meioses were available for cosegregation scoring.	cspec
PP2	N/A	Not applicable: explicitly marked Not Applicable by the HRAS VCEP v2.3.	cspec
PP3	Not met	Not met: REVEL 0.412 is below the required 0.7 threshold.	cspec revel spliceai
PP4	N/A	Not applicable: the HRAS VCEP v2.3 explicitly excludes this criterion.	cspec
PP5	N/A	Not applicable: excluded by HRAS VCEP v2.3, and no exact-variant ClinVar expert-panel pathogenic assertion exists.	cspec clinvar
BA1	Not met	Not met: absent from gnomAD, so allele frequency is below the 0.05% BA1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD, so allele frequency is below the 0.025% BS1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no healthy-adult homozygote or heterozygote observations were available.	cspec
BS3	N/A	Not applicable: the HRAS VCEP v2.3 marks BS3 Not Applicable for this gene.	cspec
BS4	Not assessed	Not assessed: no family genotypes or informative meioses were available to evaluate non-segregation.	cspec
BP1	N/A	Not applicable: this is a missense change, not a truncating variant, in a gain-of-function disorder.	cspec
BP2	Not assessed	Not assessed: no in-trans observations, phase information, or qualifying allelic data were available.	cspec
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel in a repetitive region.	cspec
BP4	Not met	Not met: REVEL 0.412 is above the <=0.3 BP4 threshold.	cspec revel spliceai
BP5	Not assessed	Not assessed: no alternate molecular diagnosis or second pathogenic variant in the patient was documented.	cspec
BP6	N/A	Not applicable: excluded by HRAS VCEP v2.3, and no exact-variant ClinVar expert-panel benign assertion exists.	cspec clinvar
BP7	N/A	Not applicable: this is a missense change, not a synonymous or non-coding variant.	cspec

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