Variant classification summary

NM_002524.5:c.183A>T

NRAS · NP_002515.1:p.(Gln61His) · NM_002524.5

GRCh37: chr1:115256528 T>A · GRCh38: chr1:114713907 T>A

Gene: NRAS Transcript: NM_002524.5

Final call

Likely Pathogenic

PM1 moderate PM2 moderate PM5 moderate PP2 supporting PP3 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.5

Protein

NP_002515.1:p.(Gln61His)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002524.5:c.183A>T (p.Gln61His) in NRAS is a missense variant in the Switch II functional domain (HRAS 57-64), a critical GTPase region where pathogenic gain-of-function variants are well-established in the RASopathy spectrum.

2

This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting the RASopathy VCEP requirement for PM2 at moderate strength.

3

Multiple different pathogenic missense variants at NRAS codon Q61 (Q61R, Q61K, Q61L) are established in the RASopathy spectrum, supporting PM5 at moderate strength.

4

PP2 is applicable to all RASopathy genes per VCEP specification, reflecting the low rate of benign missense variation in these genes.

5

REVEL predicts a damaging effect (score 0.742), and Q61 is a statistically significant cancer hotspot (cancerhotspots.org), supporting PP3 at supporting strength.

6

This variant has been reported in ClinVar with conflicting classifications: Pathogenic (1 submitter, GeneDx) and Uncertain significance (1 submitter, Hospital for Sick Children). No expert panel review is available.

7

NRAS Q61H is a well-established somatic oncogenic mutation reported 168 times in COSMIC and classified as Oncogenic (gain-of-function) by OncoKB. Functional studies per the VCEP-approved assay framework exist for NRAS but were not directly verified for this variant in the case materials.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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 per RASopathy VCEP: LOF and/or haploinsufficiency has not been clearly identified as a disease mechanism for NRAS relative to the RASopathy spectrum phenotype. This is also a missense variant, not a null variant.	cspec
PS1	Not met	PS1 requires the same amino acid change (Q61H) to be previously established as pathogenic per VCEP criteria from a different nucleotide change. No evidence of a different nucleotide change producing NRAS Q61H that has been classified as pathogenic under VCEP in the germline RASopathy context was identified. The ClinVar record for this variant (VCV000373003) has conflicting classifications (Pathogenic/Uncertain significance) with no expert panel review.	clinvar
PS2	Not assessed	No de novo occurrence report for NM_002524.5:c.183A>T (NRAS Q61H) with confirmed paternity in a RASopathy patient was identified in the case materials or literature reviewed.
PS3	Not assessed	The RASopathy VCEP has approved functional assays for NRAS (RAS Activation, MEK Activation, ERK Activation; PMIDs 19966803, 28594414, 21263000) at PS3_Supporting strength per assay. However, the approved functional study papers are not present in the case materials and could not be directly verified for variant-specific testing of NRAS Q61H. OncoKB classifies this variant as Oncogenic (gain-of-function), and NRAS Q61H is a well-established activating mutation. Cannot independently confirm variant-specific functional data from approved VCEP studies.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not assessed	No independent RASopathy-affected proband counts are available in the case materials. The ClinVar record (VCV000373003) has 2 clinical submissions but no proband-level phenotype data. PS4 under VCEP requires independent occurrence counts (>=1 for Supporting, >=3 for Moderate, >=5 for Strong) in patients with RASopathy phenotype.	clinvar
PS5	N/A	PS5 is not defined in the ClinGen RASopathy VCEP criteria specification (version 1.0). This criterion is not part of the VCEP framework for NRAS.	cspec
PM1	Met	Residue Q61 is located within the Switch II functional domain (HRAS 57-64), which is explicitly listed as an approved PM1 functional domain in the RASopathy VCEP supplemental material (Alignment-with-PM1-domains). Q61 is also a statistically significant missense hotspot at cancerhotspots.org. NRAS is in the VCEP Group 1 analogous genes (HRAS, NRAS, KRAS).	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	This variant is completely absent from all population databases surveyed (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0), satisfying the RASopathy VCEP requirement that the variant must be completely absent from all population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Met	Multiple different pathogenic missense changes at NRAS codon Q61 are established in the RASopathy spectrum (e.g., Q61R, Q61K, Q61L in HRAS/KRAS/NRAS). These are well-characterized gain-of-function pathogenic variants at the same residue. Q61H (His) is a non-conservative substitution concordant with the pathogenic direction of other Q61 missense changes. The VCEP mutual-exclusion rule (PM5 not to be used with PM1 when residue is a designated hotspot) does not apply here because Q61 is not individually designated as a mutational hotspot in the PM1 supplemental material — only the Switch II domain (57-64) is listed.	cspec oncokb
PM6	Not assessed	No de novo occurrence report (with or without confirmed parentage) was identified in the case materials or reviewed literature for this variant in a RASopathy patient.
PP1	Not assessed	No co-segregation data or family studies are available in the case materials for this variant. PP1 under VCEP requires at least 3 informative meioses at the Supporting level.
PP2	Met	PP2 is explicitly applicable to all RASopathy genes described and curated by the VCEP, including NRAS. This is a missense variant in a gene where missense variants are a common mechanism of disease (gain-of-function), with a low rate of benign missense variation at critical residues.	cspec
PP3	Met	Multiple lines of computational evidence support a deleterious effect. REVEL score 0.742 predicts damaging. Residue Q61 is a statistically significant cancer hotspot (cancerhotspots.org). COSMIC reports 168 somatic occurrences at this position. OncoKB classifies as Oncogenic. SpliceAI max delta 0.00 indicates no cryptic splice impact. BayesDel 0.130 is discordant but REVEL and hotspot evidence together provide multiple independent lines of computational support.	revel oncokb spliceai
PP4	N/A	Not applicable per RASopathy VCEP: PP4 is designated as Not Applicable for this VCEP.	cspec
PP5	N/A	Not applicable per RASopathy VCEP: PP5 is designated as Not Applicable — 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BA1	Not met	VCEP BA1 threshold is allele frequency >=0.05%. This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	VCEP BS1 threshold is allele frequency >=0.025%. This variant is completely absent from all population databases surveyed. Does not meet the frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	VCEP restricts BS2: due to variable expressivity and severity of RASopathies, general population data should not be used. Requires more than 3 instances of well-phenotyped family members. No such data is available in the case materials.
BS3	Not met	BS3 requires approved functional studies showing no damaging effect on protein function. NRAS Q61H is a well-established gain-of-function mutation (OncoKB: Oncogenic). All available evidence points toward a damaging gain-of-function effect, not a benign or normal functional outcome.	oncokb
BS4	Not assessed	No segregation data (supporting or refuting co-segregation) is available in the case materials. BS4 requires lack of segregation in affected family members.
BP1	N/A	VCEP BP1 applies to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, single/multi-exon deletion) in genes without established LOF correlation to disease. NM_002524.5:c.183A>T is a missense variant (p.Gln61His), not a truncating variant.	cspec
BP2	Not assessed	No data on whether this variant has been observed in trans with a pathogenic variant (for a dominant disorder) or in cis with a pathogenic variant is available in the case materials.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score 0.742 predicts a damaging effect. The variant is a statistically significant cancer hotspot. BayesDel 0.130 is low but does not outweigh the multiple lines of evidence supporting a deleterious effect (REVEL, hotspot status, COSMIC prevalence, OncoKB oncogenic classification). Multiple independent lines do not uniformly suggest no impact.	revel bayesdel spliceai oncokb
BP5	Not assessed	No evidence of an alternate molecular basis for disease in a patient carrying this variant was identified in the case materials.
BP6	N/A	Not applicable per RASopathy VCEP: BP6 is designated as Not Applicable — '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 for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_002524.5:c.183A>T is a missense variant (p.Gln61His), not a synonymous variant.	cspec
BP3	N/A	Skipped — BP3 applies to in-frame deletions/insertions in repetitive regions. This is a substitution variant.
PM3	N/A	Skipped — PM3 applies to recessive disorders (detected in trans with a pathogenic variant). RASopathies are dominant disorders.
PM4	N/A	Skipped — PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. This is a substitution variant.

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