Variant classification summary

NM_176795.4:c.277A>G

HRAS · NP_789765.1:p.(Ile93Val) · NM_176795.4

GRCh37: chr11:533779 T>C · GRCh38: chr11:533779 T>C

Gene: HRAS Transcript: NM_176795.4

Final call

VUS

BP4 supporting

Variant details

Gene

HRAS

Transcript

NM_176795.4

Protein

NP_789765.1:p.(Ile93Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The HRAS c.277A>G (p.Ile93Val) variant has been observed in somatic cancer once in COSMIC and has been reported in ClinVar with conflicting germline interpretations, including an expert-panel classification of uncertain significance.

2

This variant is present at very low frequency in population databases, with 2/282578 alleles in gnomAD v2.1 (0.00071%) and 4/1613210 alleles in gnomAD v4.1 (0.00025%), which is below the HRAS RASopathy BS1 threshold of 0.025% and below the BA1 threshold of 0.05%, but it is not absent from controls.

3

Computational predictors do not support a damaging effect: REVEL is 0.141, BayesDel is -0.349425, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, supporting BP4 and not meeting the PP3 threshold.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	This is a missense variant, and the HRAS RASopathy specification marks PVS1 as not applicable. Available PVS1 context does not support use of a null-variant mechanism for this variant type.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No previously established pathogenic variant causing the same amino acid change was identified, so PS1 cannot be applied from the available evidence.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with sufficient phenotype and parental testing details was identified, so PS2 cannot be applied.	cspec clinvar
PS3	Not assessed	Approved functional assay types are defined for HRAS, but no variant-specific approved functional result for p.(Ile93Val) was identified in the available evidence, so PS3 cannot be applied.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not assessed	The available evidence does not establish the number of unrelated affected individuals or a point total required for PS4, so this criterion cannot be applied.	cspec clinvar
PM1	Not met	This variant affects codon 93, which is outside the HRAS RASopathy VCEP PM1 domains (P-loop amino acids 10-17, SW1 amino acids 25-40, SW2 amino acids 57-64, and SAK amino acids 145-156). Cancer Hotspots also did not identify this residue as a statistically significant hotspot.	cspec vcep_alignment_with_pm1_domains_pptx hotspots
PM2	Not met	This variant is present in population databases, so it is not absent from controls and PM2 cannot be applied. It is seen in gnomAD v2.1 at 2/282578 alleles (AF 0.00071%) and in gnomAD v4.1 at 4/1613210 alleles (AF 0.00025%).	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the HRAS RASopathy specification.	cspec
PM4	N/A	This is a missense variant and does not cause an in-frame length change or stop-loss, so PM4 is not applicable.	cspec
PM5	Not assessed	No established pathogenic missense change at the same codon or analogous residue position was identified in the available evidence, so PM5 cannot be applied.	cspec clinvar
PM6	Not assessed	No de novo occurrence without full parental confirmation was identified from the available evidence, so PM6 cannot be applied.	cspec clinvar
PP1	Not assessed	No segregation data were identified, so PP1 cannot be applied.	cspec clinvar
PP2	N/A	PP2 is not applicable in the HRAS RASopathy specification.	cspec
PP3	Not met	Available computational evidence does not meet the HRAS RASopathy VCEP threshold for PP3. REVEL is 0.141, which is below the PP3 threshold of 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.	cspec revel spliceai
PP4	N/A	PP4 is not applicable in the HRAS RASopathy specification.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BA1	Not met	Population frequency is below the BA1 threshold. The highest observed gnomAD subpopulation frequency is 0.01385% in v2.1 and 0.00320% in v4.1, both below the BA1 threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Population frequency is below the BS1 threshold. The highest observed gnomAD subpopulation frequency is 0.01385% in v2.1 and 0.00320% in v4.1, both below the BS1 threshold of 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No data were identified showing this variant in sufficient unaffected individuals for BS2 scoring.	cspec
BS3	N/A	BS3 is not applicable in the HRAS RASopathy specification.	cspec
BS4	Not assessed	No lack-of-segregation data were identified, so BS4 cannot be applied.	cspec clinvar
BP1	N/A	BP1 in this framework is intended for truncating loss-of-function variants in genes with primarily gain-of-function disease mechanisms. This variant is missense, so BP1 is not applicable.	cspec
BP2	Not assessed	No evidence was identified for this variant occurring with an alternative molecular cause in the same gene, so BP2 cannot be applied.	cspec clinvar
BP3	N/A	BP3 is not applicable in the HRAS RASopathy specification.	cspec
BP4	Met	Computational evidence supports a benign interpretation. REVEL is 0.141, which is below the BP4 threshold of 0.3 for missense variants, BayesDel is -0.349425, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.	cspec revel bayesdel spliceai
BP5	Not assessed	No alternative molecular diagnosis or clearly different explanatory cause was identified, so BP5 cannot be applied.	cspec clinvar
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous or certain noncoding variants with no predicted splice impact. This variant is missense, so BP7 is not applicable.	cspec spliceai

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