About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.407G>A, p.(Ser136Asn)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen KRAS VCEP v1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PP2Supporting
PP2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Not classified
No source classification-combination explanation was recorded.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
11 / 1,613,106 alleles
gnomAD v4.1: 11 / 1,613,106 alleles. Recorded AF 6.81914e-06. Recorded homozygote count 0.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
4 Uncertain significance · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
In progress — evidence not uploaded yet.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55734923, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen KRAS VCEP v1.0, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 17 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
The variant is located at codon 136, outside the VCEP-approved PM1 functional domains (P-loop residues 10-17, Switch I residues 25-40).
No pathogenic variants have been established at this residue in KRAS, HRAS, or NRAS, precluding PM5 application.
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.
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).
ClinVar classifies this variant as Uncertain Significance (4 clinical laboratories) and Likely Benign (1 clinical laboratory).
No criteria match.
Met · 2
PP2 SupportingPer 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. Details ▾Hide ▴
Evidence considered
- RASopathy VCEP: PP2 is applicable to all RASopathy genes described and curated
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no splice impact)
- BayesDel: -0.256 (benign)
- REVEL: 0.274 (low
- below pathogenic threshold)
Sources
Not met · 17 · evaluated, threshold not reached
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. ClinVar classifies this variant as Uncertain Significance. Details ▾Hide ▴
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. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in literature or ClinVar submissions
Still missing
- No de novo testing data available
PS3 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. Details ▾Hide ▴
Evidence considered
- VCEP functional studies spreadsheet: approved KRAS assays cite PMIDs 20949621 and 23059812
- S136N not among studied variants
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence
Still missing
- No functional characterization of p.Ser136Asn in any VCEP-approved assay
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 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. Details ▾Hide ▴
Evidence considered
- No proband data in literature or ClinVar submissions
Still missing
- No clinical case data available
PM1 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. Details ▾Hide ▴
Evidence considered
- VCEP PM1 domains: P-loop (10-17) and Switch I (25-40)
- Ser136 is outside both
- cancerhotspots.org: residue not significant
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM2 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%). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 3/251
- 172 alleles (AF=0.00119%)
- gnomAD v4.1: 11/1
- 613
- 106 alleles (AF=0.00068%)
Sources
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. No same-residue comparator candidates were identified in ClinVar. Details ▾Hide ▴
Evidence considered
- ClinVar: no pathogenic missense variants at residue 136 in KRAS
- PM5 candidate search: 0 same-residue candidates found
Sources
clinvar ↗pm5_candidates
PM6 No assumed de novo occurrence (without confirmation of paternity and maternity) has been reported for NM_033360.4:c.407G>A in RASopathy. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in literature or ClinVar
Still missing
- No de novo data available
PP1 No co-segregation data available. RASopathy VCEP requires at least three informative meioses for PP1 at supporting strength. Details ▾Hide ▴
Evidence considered
- No segregation data in literature or ClinVar submissions
Still missing
- No family segregation studies available
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.274 (weak
- below pathogenic threshold)
- BayesDel: -0.256 (benign direction)
- SpliceAI: max delta 0.01 (no splice impact)
Sources
BA1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max AF: 0.0033% (South Asian)
- gnomAD v4.1 max AF: 0.0016% (Remaining)
- VCEP threshold: >=0.05%
Sources
BS1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max AF: 0.0033%
- gnomAD v4.1 max AF: 0.0016%
- VCEP threshold: >=0.025%
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- VCEP: BS2 requires >3 instances of well-phenotyped family members
- none available
Still missing
- No phenotyped healthy carrier data
Sources
BS3 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. Details ▾Hide ▴
Evidence considered
- VCEP functional studies: S136N not tested in any approved assay
Still missing
- No functional characterization of S136N
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4 No segregation data demonstrating lack of segregation with RASopathy phenotype are available. VCEP requires only one informative meiosis for BS4 at strong strength. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family segregation studies
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. Details ▾Hide ▴
Evidence considered
- No phase data available
Still missing
- No phase information with known pathogenic variants in KRAS
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for RASopathy. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available
Still missing
- No data on co-occurring molecular diagnoses
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 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. Details ▾Hide ▴
Evidence considered
- RASopathy VCEP v1.0: PVS1 Not Applicable
- LOF not established as RASopathy disease mechanism
Sources
PP4 VCEPPP4 is explicitly Not Applicable per the RASopathy VCEP. Patient phenotype specificity is addressed through the PS4 proband counting criterion instead. Details ▾Hide ▴
PP5 VCEPPP5 is explicitly Not Applicable per the RASopathy VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP1 N/ARASopathy 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. Details ▾Hide ▴
Evidence considered
- VCEP: BP1 applies to truncating variants only
- this is a missense variant
Sources
BP6 VCEPBP6 is explicitly Not Applicable per the RASopathy VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 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. Details ▾Hide ▴
PS5 N/APS5 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. Details ▾Hide ▴
Identifiers
- Gene
- KRAS
- Transcript
- NM_033360.4
- Coding (HGVS c.)
- NM_033360.4:c.407G>A
- Protein (HGVS p.)
- NP_203524.1:p.(Ser136Asn)
- GRCh38
- chr12:25225657 C>T
- GRCh37
- chr12:25378591 C>T
- ClinVar
- 503538
- COSMIC
- COSV55734923
Gene diagram
Every interpreted variant in KRAS, mapped onto the exon structure of NM_033360.4. Select a row to find it on the plot.
KRASNM_033360.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KRAS
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
11 / 1,613,106 alleles
AF 6.82e-06 · 0 homozygotes · FAF 3.59e-06
gnomAD v2.1
3 / 251,172 alleles
AF 1.19e-05 · 0 homozygotes · FAF 2.93e-06
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 6.8e-06 · 11 / 1,613,106 alleles · 0 hom · FAF 3.6e-06
| Remaining individuals1 / 62,440 | 1.6e-05 |
| South Asian1 / 91,070 | 1.1e-05 |
| European (non-Finnish)9 / 1,179,522 | 7.6e-06 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.2e-05 · 3 / 251,172 alleles · 0 hom · FAF 2.9e-06
| South Asian1 / 30,600 | 3.3e-05 |
| European (non-Finnish)2 / 113,546 | 1.8e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.274
- BayesDel
- -0.256
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no splice impact)
- BayesDel: -0.256 (benign)
- REVEL: 0.274 (low
- below pathogenic threshold)
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.274 (weak
- below pathogenic threshold)
- BayesDel: -0.256 (benign direction)
- SpliceAI: max delta 0.01 (no splice impact)
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
Statement
In silico
In progress — evidence not uploaded yet.
7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 22138009 ↗NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology.Febbo PG et al. · 2011No paper-specific finding is recorded.
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PMID 24033266 ↗A systematic approach to assessing the clinical significance of genetic variants.No paper-specific finding is recorded.
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PMID 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.No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
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PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.No paper-specific finding is recorded.
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PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.Stratton MR et al. · 2008No paper-specific finding is recorded.
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PMID 24366376 ↗Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
11 / 1,613,106 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
4 Uncertain significance · 1 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637576
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/503538/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25378591-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25225657-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-25225657-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_033360.4%3Ac.407G…
- OncoKB ↗www.oncokb.org/gene/KRAS/S136N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121000028
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
In progress — evidence not uploaded yet.
In silico
In progress — evidence not uploaded yet.
Functional
In progress — evidence not uploaded yet.
Somatic
In progress — evidence not uploaded yet.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Literature
In progress — evidence not uploaded yet.