Variant classification summary

NM_005343.4:c.37G>C

HRAS · NP_005334.1:p.(Gly13Arg) · NM_005343.4

GRCh37: chr11:534286 C>G · GRCh38: chr11:534286 C>G

Gene: HRAS Transcript: NM_005343.4

Final call

VUS

PS3 moderate PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

HRAS

Transcript

NM_005343.4

Protein

NP_005334.1:p.(Gly13Arg)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PS3 moderate reflects abnormal HRAS-GTP activation and ERK1/2 phosphorylation in two approved assay types.

2

VUS: PM1 moderate reflects location of residue 13 in the approved P-loop domain.

3

VUS: PM2 supporting reflects absence from gnomAD v2.1 and v4.1 controls.

4

VUS: PP3 supporting reflects a REVEL score of 0.791 above the 0.7 threshold.

Final determination: Under the HRAS VCEP Version 2.3 framework, no pathogenic rule is met by one moderate criterion plus three supporting-level criteria because the applicable rules require exactly one or at least four supporting criteria, and no benign rule is met.

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: the VCEP explicitly marks PVS1 not applicable, and this variant is missense p.(Gly13Arg), not a loss-of-function change.	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: reports document p.Gly13Arg from c.37G>C, but no independently established pathogenic p.Gly13Arg change from a different nucleotide was available.	PMID:22499344 PMID:22683711 PMID:23884457 vcep_alignment_with_pm1_domains_pptx
PS2	Not assessed	Not assessed: ClinVar labels two submissions de novo, but no proband phenotype, parental genotypes, or confirmed germline de novo event is documented.	cspec clinvar PMID:22499344 PMID:22683711
PS3	Met	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.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:22683711
PS4	Not assessed	Not 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.	cspec PMID:22499344 PMID:22683711 PMID:23884457 gnomad_v2 gnomad_v4
PM1	Met	Met at moderate: HRAS residue 13 falls within the VCEP-approved P-loop domain spanning amino acids 10-17.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	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.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the HRAS VCEP explicitly marks PM3 as not applicable, regardless of the reported mosaic lesion observations.	cspec
PM4	N/A	Not applicable: p.(Gly13Arg) is a missense substitution with no protein-length change, and PM4 addresses protein-length changes outside repetitive regions.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: the candidate search found zero alternate-residue candidates at codon 13, so neither the one-change nor two-change PM5 threshold was established.	pm5_candidates PMID:22499344 PMID:22683711 PMID:23884457 vcep_alignment_with_pm1_domains_pptx
PM6	Not assessed	Not assessed: Two ClinVar submissions are labeled de novo, but parental testing and a countable unconfirmed germline de novo observation are absent.	cspec clinvar PMID:22499344 PMID:22683711
PP1	Not assessed	Not assessed: No pedigree, relative genotypes, or informative meioses are reported, so the VCEP's minimum 3-meiosis PP1 threshold cannot be evaluated.	cspec PMID:22499344 PMID:22683711
PP2	N/A	Not applicable: the HRAS VCEP v2.3 specification explicitly excludes PP2.	cspec
PP3	Met	Met: REVEL score 0.791 meets the VCEP missense PP3 threshold of ≥0.7.	cspec revel
PP4	N/A	Not applicable: the HRAS VCEP explicitly excludes PP4 and directs phenotype evidence to PS4.	cspec
PP5	N/A	Not applicable: the HRAS VCEP prohibits PP5 use regardless of the available ClinVar pathogenic assertions.	cspec clinvar
BA1	Not met	Not 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.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not 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.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no unaffected-individual or homozygote observations are available to assign the VCEP's -4-point or -1-point BS2 outcome.	cspec
BS3	N/A	Not applicable: the HRAS VCEP Version 2.3 explicitly marks BS3 as not applicable for this framework.	cspec
BS4	Not assessed	Not assessed: No affected variant-negative relative or informative non-segregating meiosis is documented against the VCEP's one-meiosis BS4 requirement.	cspec PMID:22499344 PMID:22683711
BP1	N/A	Not applicable: p.Gly13Arg is missense, whereas the VCEP BP1 rule is restricted to truncating variant types.	cspec
BP2	Not assessed	Not assessed: no VCEP-defined BP2 point assignment or documented cis/trans phase observation is available to reach the ≥(-1)-point supporting threshold.	cspec
BP3	N/A	Not applicable: the VCEP explicitly marks BP3 not applicable, and this variant is missense rather than an in-frame indel in a repetitive region.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL score 0.791 exceeds the VCEP missense BP4 cutoff of ≤0.3.	cspec revel
BP5	Not assessed	Not assessed: no documented alternative molecular diagnosis or BP5 point total is available to evaluate the VCEP's >=(-1), >=(-2), or >=(-4) thresholds.	cspec
BP6	N/A	Not applicable: the HRAS VCEP prohibits BP6 use regardless of any reputable-source benign assertion.	cspec
BP7	N/A	Not applicable: the variant is missense, whereas VCEP BP7 covers synonymous, noncanonical intronic, and non-coding variants.	cspec

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