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KRAS
Final classification
Unclassified
KRAS c.407G>A · p.Ser136Asn
KRAS

NM_033360.4:c.407G>A (p.Ser136Asn) is a missense variant in KRAS, a RASopathy gene.

Gene
KRAS
Transcript
NM_033360.4
HGVS · transcript:coding
NM_033360.4:c.407G>A
Consequence
N/A
exon NC_000012.11
GRCh38
chr12:25225657 C>T
GRCh37
chr12:25378591 C>T
Classification rationale
PP2 BP4 Unclassified
KRAS c.407G>A · exon NC_000012.11

NM_033360.4:c.407G>A (p.Ser136Asn) is a missense variant in KRAS, a RASopathy gene. 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).1 The variant is located at codon 136, outside the VCEP-approved PM1 functional domains (P-loop residues 10-17, Switch I residues 25-40).2 No pathogenic variants have been established at this residue in KRAS, HRAS, or NRAS, precluding PM5 application.3 No de novo occurrences, segregation data, case-control studies, or functional characterization are available for this variant. 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.4 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).5 ClinVar classifies this variant as Uncertain Significance (4 clinical laboratories) and Likely Benign (1 clinical laboratory).6

PP2 + BP4 Unclassified
2 cspec ↗vcep_alignment_with_pm1_domains_pptx
5 spliceai ↗bayesdelrevel
Gene diagram · NM_033360.4 · variants mapped to exon structure
KRAS NM_033360.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
PP2 supporting Pathogenic
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.
RASopathy VCEP: PP2 is applicable to all RASopathy genes described and curated
BP4 supporting Benign
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: max delta 0.01 (no splice impact)BayesDel: -0.256 (benign)REVEL: 0.274 (low
Assessed · not applied
Pathogenic
PS1 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.
PS2 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 The VCEP-approved functional studies for KRAS (RAS Activation, MEK Activation, ERK Activation assays) reference PMIDs 20949621 and 23059812 for assay validation.
PS4 No independent proband occurrences meeting RASopathy VCEP thresholds (>=1 for supporting, >=3 for moderate, >=5 for strong) have been identified.
PM1 Position p.Ser136 lies outside the VCEP-approved functional domains for PM1.
PM2 RASopathy VCEP requires complete absence from all population databases for PM2 application.
PM5 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.
PM6 No assumed de novo occurrence (without confirmation of paternity and maternity) has been reported for NM_033360.4:c.407G>A in RASopathy.
PP1 No co-segregation data available.
PP3 Multiple lines of computational evidence do not support a deleterious effect.
Benign
BA1 RASopathy VCEP BA1 threshold is allele frequency >=0.05%.
BS1 RASopathy VCEP BS1 threshold is allele frequency >=0.025%.
BS2 RASopathy VCEP specifies that general population data should not be used for BS2 due to variable expressivity and severity of RASopathies.
BS3 No VCEP-approved functional studies demonstrate a lack of damaging effect for p.Ser136Asn.
BS4 No segregation data demonstrating lack of segregation with RASopathy phenotype are available.
BP2 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.
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for RASopathy.
N/A · 6 PVS1 · PP4 · PP5 · BP1 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.81914e-06; MAF= 0.00068%, 11/1613106 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60154e-05; MAF= 0.00160%, 1/62440 alleles, homozygotes = 0); grpmax FAF= 3.59e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.1944e-05; MAF= 0.00119%, 3/251172 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26797e-05; MAF= 0.00327%, 1/30600 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00068% · 11 / 1,613,106
0 hom · FAF 0.00036%
Remaining individuals
1 / 62,440
0.0016%
South Asian
1 / 91,070
0.0011%
European (non-Finnish)
9 / 1,179,522
0.00076%
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0012% · 3 / 251,172
0 hom · FAF 0.00029%
South Asian
1 / 30,600
0.0033%
European (non-Finnish)
2 / 113,546
0.0018%
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
In progress — evidence not uploaded yet.
SpliceAI screenshot
In silico
In progress — evidence not uploaded yet.
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
In progress — evidence not uploaded yet.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
In progress — evidence not uploaded yet.
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 7 PMIDs not cited in assessment
22138009 ↗ NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology. CLINVAR
24033266 ↗ A systematic approach to assessing the clinical significance of genetic variants. CLINVAR
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR
18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR
24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR