LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-01
Case ID: NM_033360.4_c.407G_A_20260801_153536
Framework: ACMG/AMP 2015
Variant classification summary

KRAS  · NP_203524.1:p.(Ser136Asn)  · NM_033360.4
GRCh37: chr12:25378591 C>T  ·  GRCh38: chr12:25225657 C>T
Gene: KRAS Transcript: NM_033360.4
Final call
All criteria require review: For research and educational purposes only.
Variant details
Gene
KRAS
Transcript
NM_033360.4
Protein
NP_203524.1:p.(Ser136Asn)
gnomAD AF
6.8191426973800855e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_033360.4:c.407G>A (p.Ser136Asn) is a missense variant in KRAS, a RASopathy gene.
2
The variant is present in population databases (gnomAD v2.1: 3/251,172 alleles, AF=0.00119%; gnomAD v4.1: 11/1,613,106 alleles, AF=0.00068%), precluding application of PM2 (VCEP requires complete absence).
3
The variant is located at codon 136, outside the VCEP-approved PM1 functional domains (P-loop residues 10-17, Switch I residues 25-40).
4
No pathogenic variants have been established at this residue in KRAS, HRAS, or NRAS, precluding PM5 application.
5
No de novo occurrences, segregation data, case-control studies, or functional characterization are available for this variant.
6
PP2 is met at supporting strength per VCEP specification, as KRAS is a RASopathy gene where missense variants are a common disease mechanism with a low rate of benign missense variation.
7
BP4 is met at supporting strength: multiple lines of computational evidence suggest no impact on the gene product (SpliceAI max delta 0.01, BayesDel -0.256, REVEL 0.274).
8
ClinVar classifies this variant as Uncertain Significance (4 clinical laboratories) and Likely Benign (1 clinical laboratory).
Final determination:
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 PVS1 is explicitly Not Applicable per the ClinGen RASopathy VCEP v1.0. Loss-of-function and/or haploinsufficiency has not been clearly identified as a disease mechanism for KRAS relative to the RASopathy spectrum phenotype. Additionally, this is a missense variant (c.407G>A, p.Ser136Asn), not a null variant.
cspec
PS1 Not met No previously established pathogenic variant with the same amino acid change (p.Ser136Asn) has been identified in KRAS, HRAS, or NRAS per RASopathy VCEP criteria. ClinVar classifies this variant as Uncertain Significance.
clinvar cspec
PS2 Not met No de novo occurrence with confirmed paternity has been reported for NM_033360.4:c.407G>A in a patient with RASopathy and no family history.
PS3 Not met The VCEP-approved functional studies for KRAS (RAS Activation, MEK Activation, ERK Activation assays) reference PMIDs 20949621 and 23059812 for assay validation. The specific variant p.Ser136Asn has not been functionally characterized in any VCEP-approved assay or published functional study. No variant-specific or systematically characterized range-based functional evidence exists.
cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 Not met No independent proband occurrences meeting RASopathy VCEP thresholds (>=1 for supporting, >=3 for moderate, >=5 for strong) have been identified. No case reports of individuals with RASopathy and this variant are available.
PS5 N/A PS5 is not included in the RASopathy VCEP specifications. The analogous criterion PP5 is explicitly Not Applicable per VCEP. No reputable source reports this variant as pathogenic; ClinVar classification is Uncertain Significance.
cspec clinvar
PM1 Not met Position p.Ser136 lies outside the VCEP-approved functional domains for PM1. The approved domains for Group 1 genes (HRAS, NRAS, KRAS) are the P-loop (residues 10-17, HRAS numbering) and Switch I (residues 25-40, HRAS numbering). Ser136 is in the C-terminal region, distant from both domains. It is not a statistically significant mutational hotspot per cancerhotspots.org.
cspec vcep_alignment_with_pm1_domains_pptx
PM2 Not met RASopathy VCEP requires complete absence from all population databases for PM2 application. This variant is present in gnomAD v2.1 (3/251,172 alleles, AF=0.00119%) and gnomAD v4.1 (11/1,613,106 alleles, AF=0.00068%).
gnomad_v2 gnomad_v4
PM5 Not met No pathogenic missense variant has been established at residue p.Ser136 in KRAS (or at the analogous residue in HRAS/NRAS) per RASopathy VCEP criteria. No same-residue comparator candidates were identified in ClinVar.
clinvar pm5_candidates
PM6 Not met No assumed de novo occurrence (without confirmation of paternity and maternity) has been reported for NM_033360.4:c.407G>A in RASopathy.
PP1 Not met No co-segregation data available. RASopathy VCEP requires at least three informative meioses for PP1 at supporting strength.
PP2 Met Per RASopathy VCEP specification, PP2 is applicable to all RASopathy genes. KRAS has a low rate of benign missense variation and missense variants are a common mechanism of disease in RASopathies.
cspec
PP3 Not met Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.274 (below typical pathogenic thresholds), BayesDel score is -0.256 (benign prediction), and SpliceAI predicts no splice impact (max delta 0.01). The in silico evidence is mixed and insufficient to support pathogenicity.
revel bayesdel spliceai
PP4 N/A PP4 is explicitly Not Applicable per the RASopathy VCEP. Patient phenotype specificity is addressed through the PS4 proband counting criterion instead.
cspec
PP5 N/A PP5 is explicitly Not Applicable per the RASopathy VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
cspec
BA1 Not met RASopathy VCEP BA1 threshold is allele frequency >=0.05%. The maximum observed population frequency for this variant is 0.0033% (gnomAD v2.1 South Asian), well below the stand-alone benign threshold.
gnomad_v2 gnomad_v4 cspec
BS1 Not met RASopathy VCEP BS1 threshold is allele frequency >=0.025%. The maximum observed population frequency for this variant is 0.0033%, well below the strong benign threshold.
gnomad_v2 gnomad_v4 cspec
BS2 Not met RASopathy VCEP specifies that general population data should not be used for BS2 due to variable expressivity and severity of RASopathies. No data on well-phenotyped healthy adult carriers are available.
cspec
BS3 Not met No VCEP-approved functional studies demonstrate a lack of damaging effect for p.Ser136Asn. The VCEP-approved KRAS functional assays (RAS, MEK, ERK activation) have not characterized this variant.
cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4 Not met No segregation data demonstrating lack of segregation with RASopathy phenotype are available. VCEP requires only one informative meiosis for BS4 at strong strength.
BP1 N/A RASopathy VCEP specifies BP1 for truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, entire gene or multi-exon deletion) in genes without established LOF correlation to disease. This variant is a missense substitution (c.407G>A, p.Ser136Asn), not a truncating variant.
cspec
BP2 Not met No observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP4 Met Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splice effect (max delta 0.01), BayesDel score is -0.256 (benign prediction), and REVEL score is 0.274 (below pathogenic threshold). Per VCEP caveat, BP4 can be used only once in any evaluation of a variant.
spliceai bayesdel revel cspec
BP5 Not met No evidence that this variant has been found in a case with an alternate molecular basis for RASopathy.
BP6 N/A BP6 is explicitly Not Applicable per the RASopathy VCEP 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. This variant is a missense substitution (c.407G>A, p.Ser136Asn), not a synonymous variant.
cspec
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