Variant classification summary

NM_002524.5:c.181C>A

NRAS · NP_002515.1:p.(Gln61Lys) · NM_002524.5

GRCh37: chr1:115256530 G>T · GRCh38: chr1:114713909 G>T

Gene: NRAS Transcript: NM_002524.5

Final call

VUS

PM1 moderate PP3 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.5

Protein

NP_002515.1:p.(Gln61Lys)

gnomAD AF

6.205406398270429e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 moderate: residue 61 is within the VCEP-approved Switch II domain (57-64).

2

PP3 supporting: REVEL 0.841 exceeds the VCEP missense threshold of 0.7.

Final determination: Under the NRAS VCEP Version 2.3 framework, PM1 at moderate strength plus PP3 at supporting strength satisfies neither a pathogenic nor a benign combination rule, resulting in VUS.

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 NRAS VCEP explicitly marks PVS1 as not applicable, and this variant is the missense substitution p.(Gln61Lys).	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: no distinct nucleotide change producing NRAS Q61K was established as a previously pathogenic variant under the VCEP rule.	cspec
PS2	Not assessed	Not assessed: no documented proband phenotype, parental genotypes, maternity, paternity, or family-history data are available to establish de novo occurrence.	cspec
PS3	Not assessed	Not assessed: exact-variant functional studies exist, but no approved NRAS assay entry was found for c.181C>A, p.Gln61Lys, or p.Q61K.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:22718121
PS4	Not assessed	Not assessed: no variant-specific affected-versus-control counts, OR/RR with confidence interval, or qualifying unrelated RASopathy case series are available for the >5.0 PS4 rule.	cspec PMID:23515407
PM1	Met	Met at moderate strength: NRAS residue 61 falls within the VCEP-approved Switch II functional domain spanning residues 57-64.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	Not met: gnomAD v4.1 all-comers reports 1/1,611,498 alleles, so the variant is not absent from the VCEP-specified default gnomAD control dataset.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the NRAS VCEP marks PM3 Not Applicable for this specification.	cspec
PM4	Not met	Not met: c.181C>A is a missense substitution producing p.(Gln61Lys), with no protein length change or in-frame indel.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: codon 61 alternatives were reported, but no comparator was established as likely pathogenic under the VCEP PM5 thresholds.	cspec PMID:23515407 pm5_candidates
PM6	Not assessed	Not assessed: no clinical or parental evidence establishes assumed de novo status, so the VCEP's PM6 point score cannot be assigned.	cspec
PP1	Not assessed	Not assessed: zero informative meioses or affected-relative segregation results are documented against the VCEP minimum of 3 informative meioses for supporting PP1.	cspec
PP2	N/A	Not applicable: the NRAS VCEP explicitly designates PP2 as not applicable.	cspec
PP3	Met	Met at Supporting: REVEL is 0.841, exceeding the NRAS VCEP PP3 missense threshold of 0.7.	cspec revel
PP4	N/A	Not applicable: the NRAS VCEP explicitly excludes PP4 and directs phenotype-specific evidence to PS4.	cspec
PP5	N/A	Not applicable: the NRAS VCEP prohibits PP5 use regardless of available pathogenic reports or classifications.	cspec
BA1	Not met	Not met: gnomAD v4.1 allele frequency is 0.0000620541% (1/1,611,498), below the VCEP BA1 threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 allele frequency is 0.0000620541% (1/1,611,498), below the VCEP BS1 threshold of 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows 0 homozygotes, but the VCEP provides no operational BS2 evidence rule or qualifying healthy-adult observation for point assignment.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the NRAS VCEP explicitly marks BS3 as not applicable and the functional-studies table records BS3_NA.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no affected-family-member genotypes or informative meiosis are documented to demonstrate the VCEP-required lack of segregation.	cspec
BP1	N/A	Not applicable: c.181C>A p.Q61K is missense, whereas the VCEP BP1 rule applies to specified truncating variant types.	cspec
BP2	Not assessed	Not assessed: no phase or pathogenic-allele observation and no VCEP BP2 point total are documented, so the ≥(-1), ≥(-2), or ≥(-4) thresholds cannot be evaluated.	cspec
BP3	N/A	Not applicable: the NRAS VCEP explicitly marks BP3 as not applicable, and this variant is a missense substitution.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL is 0.841, above the NRAS VCEP BP4 missense cutoff of 0.3.	cspec revel
BP5	Not assessed	Not assessed: no documented alternative causative variant or VCEP BP5 point assignment is available to evaluate the applicable point thresholds.	cspec
BP6	N/A	Not applicable: the NRAS VCEP prohibits BP6 use regardless of any reputable benign report.	cspec
BP7	N/A	Not applicable: c.181C>A is missense, whereas BP7 covers synonymous, noncanonical intronic, or non-coding variants.	cspec

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