Variant classification summary

NM_033360.3:c.179G>T

KRAS · NP_203524.1:p.(Gly60Val) · NM_033360.3

GRCh37: chr12:25380279 C>A · GRCh38: chr12:25227345 C>A

Gene: KRAS Transcript: NM_033360.3

Final call

Likely Pathogenic

PS2 moderate PS4 supporting PM1 moderate PM5 moderate PP3 supporting

Variant details

Gene

KRAS

Transcript

NM_033360.3

Protein

NP_203524.1:p.(Gly60Val)

gnomAD AF

1.8586577517180193e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_033360.3:c.179G>T (p.Gly60Val) is a missense variant in KRAS identified in a single de novo proband with Noonan syndrome and lethal hypertrophic cardiomyopathy (Nosan et al. 2013).

2

The variant affects Gly60, which resides in the Switch II domain (AA 57–64), a critical functional domain per RASopathy VCEP specifications (PM1_Moderate).

3

At least two different pathogenic missense changes (p.Gly60Ser, p.Gly60Arg) have been reported at the same codon in RASopathy patients, satisfying PM5 at Moderate strength.

4

Parental genotyping confirmed the variant occurred de novo, meeting PS2 at Moderate strength (1 de novo point per VCEP rules).

5

The variant is observed in a single RASopathy proband, meeting PS4 at Supporting strength (≥1 point per VCEP rules).

6

REVEL in silico score of 0.879 exceeds the VCEP threshold of ≥0.7, meeting PP3 at Supporting strength.

7

The variant is present at extremely low frequency in gnomAD (v2.1: 1/251,328; v4.1: 3/1,614,068), which is below benign population thresholds but above the PM2 absence requirement.

8

Applying the RASopathy VCEP classification rules: three Moderate criteria (PS2_Moderate, PM1, PM5) plus two Supporting criteria (PS4_Supporting, PP3) are met. Per VCEP Rule13, ≥3 Moderate criteria yields a classification of Likely Pathogenic.

Final determination: Rule13 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Pathogenic.

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	CSPEC RASopathy VCEP v2.3.0 designates PVS1 as Not Applicable. KRAS RASopathies have a gain-of-function disease mechanism; this is a missense variant (p.Gly60Val) and does not fall into null-variant buckets.	cspec
PS1	Not met	PS1 requires the same amino acid change as a previously established pathogenic variant. G60V has not been previously established as a germline pathogenic variant in KRAS or analogous RAS genes. G60S and G60R are established pathogenic changes at the same residue but constitute different amino acid substitutions.	PMID:24382853
PS2	Met	One de novo observation confirmed by parental genotyping in an infant with Noonan syndrome and lethal hypertrophic cardiomyopathy (Nosan et al. 2013). Per RASopathy VCEP PS2 rules, 1 de novo point confers Moderate strength.	PMID:24382853
PS3	Not assessed	No variant-specific functional assay data for KRAS G60V were identified in the available literature. The RASopathy VCEP-approved functional assays (RAS activation, MEK/ERK activation) list PMIDs 20949621 and 23059812 for KRAS, but full texts were not available to confirm G60V was tested.
PS4	Met	One well-documented RASopathy proband identified — an infant with Noonan syndrome, dysmorphic features, and lethal HCM harboring a de novo G60V variant (Nosan et al. 2013). Per VCEP PS4 point-based rules, ≥1 point confers Supporting strength. The variant is also reported in ClinVar as Pathogenic/Likely Pathogenic by 7 clinical laboratories.	PMID:24382853 clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion and is not defined in the RASopathy VCEP v2.3.0 specifications.
PM1	Met	p.Gly60 is located within the Switch II (SW2) domain (amino acids 57–64), a critical and well-established functional domain per RASopathy VCEP specifications. SW2 is one of four domains (P-loop, SW1, SW2, SAK) approved for PM1 application at Moderate strength.	cspec
PM2	Not met	The RASopathy VCEP PM2 rule requires the variant to be absent from gnomAD controls. G60V is present in gnomAD v2.1 (1/251,328 alleles; AF=3.98×10⁻⁶) and gnomAD v4.1 (3/1,614,068 alleles; AF=1.86×10⁻⁶), therefore PM2 criteria are not satisfied.	gnomad_v2 gnomad_v4
PM5	Met	At least two different pathogenic missense changes have been reported at codon 60 — p.Gly60Ser and p.Gly60Arg — in individuals with Noonan syndrome and cardio-facio-cutaneous syndrome (cited in Nosan et al. 2013, referencing Kratz et al. 2009 and Niihori et al. 2006). Per VCEP PM5 rules, ≥1 pathogenic residue change at the same codon confers Moderate strength.	PMID:24382853
PM6	Not assessed	The single de novo event reported in Nosan et al. 2013 was applied under PS2. Applying the same event under PM6 would constitute double-counting. No additional independent de novo observations were identified.
PP1	Not met	No segregation data are available. The only reported case is de novo (Nosan et al. 2013), precluding co-segregation analysis. Per VCEP, ≥3 informative meioses are required for Supporting strength.
PP2	N/A	CSPEC RASopathy VCEP v2.3.0 designates PP2 as Not Applicable.	cspec
PP3	Met	REVEL score of 0.879 exceeds the VCEP threshold of ≥0.7 for PP3 at Supporting strength. SpliceAI max delta score is 0.25, indicating minimal predicted splicing impact, which does not alter the REVEL-based assessment.	revel spliceai
PP4	N/A	CSPEC RASopathy VCEP v2.3.0 designates PP4 as Not Applicable.	cspec
PP5	N/A	CSPEC RASopathy VCEP v2.3.0 designates PP5 as Not Applicable.	cspec
BA1	Not met	GnomAD filtering allele frequency (v2.1: 3.98×10⁻⁶; v4.1: 1.86×10⁻⁶) is far below the VCEP BA1 threshold of ≥0.05%. The variant is extremely rare in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	GnomAD filtering allele frequency (v2.1: 3.98×10⁻⁶; v4.1: 1.86×10⁻⁶) is far below the VCEP BS1 threshold of ≥0.025%. The variant is too rare in population databases to support a benign interpretation.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence of the variant observed in a healthy adult individual in a recessive or X-linked disorder, nor observed in trans with a pathogenic variant for a fully penetrant dominant disorder. The VCEP BS2 point-based scoring requires evidence of such observations.
BS3	N/A	CSPEC RASopathy VCEP v2.3.0 designates BS3 as Not Applicable.	cspec
BS4	Not met	No evidence of non-segregation with disease in affected family members. The only reported case is de novo, which does not provide segregation information for BS4 application. Per VCEP, one informative meiosis demonstrating lack of segregation would confer Strong benign evidence.
BP1	N/A	The RASopathy VCEP explicitly states BP1 has contraindications for use with RASopathies. BP1 is restricted to truncating variants in genes with established loss-of-function disease correlation. KRAS RASopathies have a gain-of-function mechanism, and this variant is missense, not truncating.	cspec
BP2	Not met	No evidence of the variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. The VCEP BP2 point-based scoring requires such observations.
BP4	Not met	REVEL score of 0.879 exceeds the VCEP BP4 threshold of ≤0.3. Multiple in silico predictions support a deleterious effect rather than a benign one. BayesDel score of 0.303 is near the borderline but does not independently support BP4.	revel bayesdel
BP5	Not met	No evidence of an alternative molecular cause for the observed RASopathy phenotype. The VCEP BP5 point-based scoring requires a documented alternative molecular diagnosis.
BP6	N/A	CSPEC RASopathy VCEP v2.3.0 designates BP6 as Not Applicable.	cspec
BP7	N/A	c.179G>T is a missense variant (p.Gly60Val), not a synonymous variant. BP7 applies exclusively to synonymous variants with no predicted splice impact.
BP3	N/A	CSPEC RASopathy VCEP v2.3.0 designates BP3 as Not Applicable — no known benign repetitive areas in RASopathy genes. Variant is a substitution, not an in-frame indel.	cspec
PM3	N/A	CSPEC RASopathy VCEP v2.3.0 designates PM3 as Not Applicable. RASopathies are autosomal dominant disorders; PM3 (in trans with pathogenic variant) is not applicable.	cspec
PM4	N/A	Skipped per adjudication instructions. This is a substitution variant, not a protein-length-altering change.

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