NM_001130442.2:c.374T>C

HRAS · NP_001123914.1:p.(Val125Ala) · NM_001130442.2

GRCh37: chr11:533529 A>G · GRCh38: chr11:533529 A>G

Gene: HRAS Transcript: NM_001130442.2

Final call

VUS

PP2 supporting

Variant details

Gene

HRAS

Transcript

NM_001130442.2

Protein

NP_001123914.1:p.(Val125Ala)

gnomAD AF

1.2392894410061048e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PP2 was applied at supporting strength per RASopathy VCEP specification, as PP2 is applicable to all RASopathy genes curated by this expert panel.

The variant p.Val125Ala is present in gnomAD v4.1 at extremely low frequency (2/1,613,828 alleles; AF = 1.24e-6), precluding PM2 (requires complete absence per VCEP) but remaining far below BA1 (>=0.05%) and BS1 (>=0.025%) thresholds.

No functional studies have characterized p.Val125Ala in any VCEP-approved assay; PS3 and BS3 cannot be applied.

The variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories, ClinVar ID 981547) with criteria provided by a single submitter. No expert panel review has been performed.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, 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	The ClinGen RASopathy VCEP specifies PVS1 as not applicable for RASopathy genes; LOF/haploinsufficiency has not been clearly identified as a disease mechanism for the RASopathy spectrum phenotype. Additionally, this is a missense variant (p.Val125Ala), which does not fall into null-variant categories.	cspec
PS1	Not met	No previously established pathogenic variant with the same amino acid change (p.Val125Ala) has been identified in HRAS. No analogous pathogenic missense at this position has been reported in Group 1 genes (HRAS, NRAS, KRAS).	clinvar cspec
PS2	Not met	No de novo occurrence with confirmed paternity has been reported in the literature for this variant. ClinVar submissions do not include de novo annotation.	clinvar
PS3	Not met	The RASopathy VCEP-approved functional studies (RAS Activation Assay, MEK Activation Assay, ERK Activation Assay) have been validated for HRAS, but the specific variant p.Val125Ala (V125A) is not among the validation controls tested in any approved study. No functional data have been published for this exact variant in any VCEP-approved assay. Per VCEP READ ME, assays not listed lack sufficient historical evidence to evaluate functional impact of a given variant and may only be sufficient for PS3_Supporting; however, without any assay data for V125A, even supporting-level evidence cannot be applied.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec oncokb
PS4	Not met	No independent occurrences meeting the VCEP threshold have been identified. The variant has been reported in ClinVar as Uncertain significance by 2 clinical laboratories but no specific proband counts or case-level data are available. No published case reports or case series describe individuals with this variant.	clinvar
PS5	N/A	PS5 is not included in the ClinGen RASopathy VCEP specification. The criterion is not applicable under this framework.	cspec
PM1	Not met	Position 125 is not located within a VCEP-approved PM1 functional domain. The approved domains for HRAS are the P-loop (residues 10-17) and Switch I (residues 25-40). Position 125 lies in the C-terminal region of HRAS outside these domains. Cancerhotspots.org does not identify this residue as a statistically significant hotspot.	vcep_alignment_with_pm1_domains_pptx cspec
PM2	Not met	The RASopathy VCEP requires complete absence from all population databases for PM2 application. The variant is present in gnomAD v4.1 with 2 alleles (AF = 1.24e-6, 2/1,613,828 alleles in the European non-Finnish population), thus it is not completely absent.	gnomad_v4 cspec
PM5	Not met	No pathogenic missense variant at the same amino acid residue (position 125) has been identified in HRAS. PM5 candidate search returned zero same-residue comparator variants. No analogous pathogenic missense at this position has been identified in Group 1 genes (HRAS, NRAS, KRAS).	pm5_candidates cspec
PM6	Not met	No assumed or confirmed de novo occurrence has been reported in the literature for this variant. ClinVar submissions do not include de novo annotation.	clinvar
PP1	Not met	No co-segregation data are available. The VCEP requires at least three informative meioses for PP1_Supporting; no family studies have been reported for this variant.	clinvar
PP2	Met	The RASopathy VCEP specifies PP2 as applicable to all RASopathy genes curated in the specification. HRAS is a RASopathy gene, and this is a missense variant (p.Val125Ala). Per VCEP: 'PP2 is applicable to all RASopathy genes described and curated herein.'	cspec
PP3	Not met	The VCEP requires multiple lines of computational evidence supporting a deleterious effect. REVEL score (0.879) supports a deleterious effect, but BayesDel (0.122) is equivocal and does not clearly support pathogenicity. SpliceAI (max delta 0.00) predicts no splice impact. HCI prior is unavailable for HRAS. Only one in silico predictor (REVEL) clearly supports a deleterious effect, which does not constitute multiple lines of evidence.	revel bayesdel spliceai cspec
PP4	N/A	The RASopathy VCEP specifies PP4 as Not Applicable for this VCEP. Per the specification: 'This criterion is not applicable to the RASopathies. See PS4 criterion for proband counting options.'	cspec
PP5	N/A	The RASopathy VCEP specifies PP5 as Not Applicable for this VCEP. Per the specification: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BA1	Not met	The VCEP BA1 threshold is allele frequency >= 0.05%. The variant frequency in gnomAD v4.1 is 1.24e-6 (0.00012%), far below the stand-alone benign threshold.	gnomad_v4 cspec
BS1	Not met	The VCEP BS1 threshold is allele frequency >= 0.025%. The variant frequency in gnomAD v4.1 is 1.24e-6 (0.00012%), an order of magnitude below the strong benign threshold.	gnomad_v4 cspec
BS2	Not met	The VCEP specifies that general population data should not be used for BS2 due to variable expressivity and severity of RASopathies. Clinical laboratories are encouraged to accumulate more than 3 instances of well-phenotyped family members before applying this criterion. No such data are available for this variant.	cspec
BS3	Not met	No VCEP-approved functional studies have been performed for this variant. The RASopathy VCEP-approved functional assays for HRAS have not tested p.Val125Ala. No evidence exists that this variant has no damaging effect on protein function.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
BS4	Not met	The VCEP requires one informative meiosis demonstrating lack of segregation. No family studies or segregation data are available for this variant.	cspec
BP1	N/A	The VCEP specifies BP1 for truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, gene/exon deletion) in genes without established LOF correlation to disease. This is a missense variant (p.Val125Ala) and does not meet the variant type requirements for BP1.	cspec
BP2	Not met	No evidence that this variant has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern.	clinvar
BP4	Not met	The VCEP requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL (0.879) predicts a deleterious effect, which contradicts the requirement. While SpliceAI (max delta 0.00) predicts no splice impact and BayesDel (0.122) is equivocal, the REVEL score alone precludes multiple lines of evidence suggesting no impact.	revel bayesdel spliceai cspec
BP5	Not met	No evidence that this variant has been found in a case with an alternate molecular basis for disease. No proband-level clinical data are available.	clinvar
BP6	N/A	The RASopathy VCEP specifies BP6 as Not Applicable for this VCEP. Per the specification: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BP7	N/A	BP7 applies to synonymous (silent) variants or intronic/non-coding variants for which splicing prediction algorithms predict no impact. This is a missense variant (c.374T>C, p.Val125Ala) and does not meet the variant type requirements for BP7.	cspec

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