About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.508A>T, p.(Met170Leu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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 v2.3.0. 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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Computational evidence supports BP4. REVEL is 0.294, which is below the KRAS BP4 threshold of 0.3, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04. BayesDel is 0.164958 and does not outweigh the VCEP-approved benign computational threshold.
Recorded classification: Uncertain significance
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: BP4 supporting; no rule matched the adjudicated criteria.
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
10 / 1,611,476 alleles
gnomAD v4.1: 10 / 1,611,476 alleles. Recorded AF 6.20549e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No listed criterion applied
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
3 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KRAS, a GTPase which functions as an upstream regulator of the MAPK pathway, is frequently mutated in various cancer types including lung, colorectal
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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 v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 7 not met · 9 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The KRAS c.508A>T (p.Met170Leu) variant has been reported in ClinVar and is classified there as uncertain significance, including an expert-panel submission from the ClinGen RASopathy Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (10/1,611,476 alleles; AF 0.00062%), which is below the KRAS BA1 threshold of 0.05% and the BS1 threshold of 0.025%.
RASopathy VCEP-approved KRAS functional assay classes are available, but no variant-specific approved functional result for p.(Met170Leu) was identified in the reviewed functional evidence, so functional pathogenic evidence was not applied.
Computational evidence supports a benign prediction because REVEL is 0.294, below the KRAS BP4 threshold of 0.3, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04; BayesDel was 0.164958 as additional computational context.
No criteria match.
Met · 1
BP4 SupportingComputational evidence supports BP4. REVEL is 0.294, which is below the KRAS BP4 threshold of 0.3, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04. BayesDel is 0.164958 and does not outweigh the VCEP-approved benign computational threshold. Details ▾Hide ▴
Rule
KRAS CSPEC BP4: for missense variants, REVEL at most 0.3.
Evidence considered
- REVEL score 0.294.
- SpliceAI max delta 0.04.
- BayesDel score 0.164958.
Sources
Not met · 7 · evaluated, threshold not reached
PS1 No previously established pathogenic or likely pathogenic variant with the same amino acid change was identified from the available records, so PS1 is not met. Details ▾Hide ▴
Rule
KRAS CSPEC PS1: same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar record reviewed for p.Met170Leu
- no same-amino-acid alternative assertion was identified in the available materials.
Still missing
- A broader manual search across expert-curated same-amino-acid assertions could further confirm the absence of a qualifying comparator.
Sources
PM1 p.(Met170Leu) is outside the KRAS RASopathy VCEP PM1 domains (P-loop residues 10-17, Switch I residues 25-40, Switch II residues 57-64, and SAK residues 145-156), and no statistically significant hotspot at residue 170 was identified. Details ▾Hide ▴
Rule
KRAS CSPEC PM1: moderate only for P-loop (AA 10-17), SW1 (AA 25-40), SW2 (AA 57-64), or SAK (AA 145-156).
Evidence considered
- KRAS CSPEC limits PM1 to P-loop
- SW1
- SW2
- and SAK domains.
- Met170 lies outside the listed PM1 domains.
- Cancer Hotspots review found no hotspot row for KRAS M170.
Sources
PM2 This variant is not absent from controls because it is present in gnomAD v4.1 at 10/1,611,476 alleles (AF 0.00062%), so the KRAS PM2 requirement for absence from controls is not met. Details ▾Hide ▴
Rule
KRAS CSPEC PM2: Supporting only when the variant is absent from gnomAD.
Evidence considered
- Absent from gnomAD v2.1.
- Present in gnomAD v4.1 with total AF 6.20549e-06.
Sources
PM5 No different pathogenic or likely pathogenic missense change at KRAS codon 170 was identified in the available same-residue review, so PM5 is not met. Details ▾Hide ▴
Rule
KRAS CSPEC PM5: Moderate for one pathogenic/likely pathogenic residue change at the same codon; Strong for at least two different pathogenic/likely pathogenic residue changes at the same codon observed in at least 5 probands.
Evidence considered
- Available same-residue review did not identify qualifying codon 170 comparators.
- ClinVar review materials did not show another established pathogenic missense change at Met170.
Still missing
- A broader manual same-codon review could further confirm the absence of qualifying codon 170 comparators.
Sources
PP3 Available computational evidence does not support a damaging effect under the KRAS VCEP rule because REVEL is 0.294, which is below the PP3 threshold of 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04. Details ▾Hide ▴
Rule
KRAS CSPEC PP3: missense REVEL at least 0.7; for splicing, predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.294.
- SpliceAI max delta 0.04.
- BayesDel score 0.164958 was available as additional computational context.
Sources
BA1 The population frequency does not meet the BA1 threshold. In gnomAD v4.1 the total allele frequency is 0.00062%, and the highest observed population frequency is 0.01653%, both below the KRAS BA1 threshold of 0.05%. Details ▾Hide ▴
Rule
KRAS CSPEC BA1: filtering allele frequency at least 0.05%.
Evidence considered
- gnomAD v4.1 total AF 6.20549e-06.
- Highest observed subpopulation AF 0.000165289 in Middle Eastern individuals.
Sources
BS1 The population frequency is below the KRAS BS1 threshold. In gnomAD v4.1 the total allele frequency is 0.00062% and the highest observed population frequency is 0.01653%, both below the BS1 threshold of 0.025%. Details ▾Hide ▴
Rule
KRAS CSPEC BS1: filtering allele frequency at least 0.025%.
Evidence considered
- gnomAD v4.1 total AF 6.20549e-06.
- Highest observed subpopulation AF 0.000165289 in Middle Eastern individuals.
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence with the phenotype and parental confirmation was identified, so PS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
KRAS CSPEC PS2 uses a point-based de novo framework.
Evidence considered
- ClinVar summary provides classification information but no de novo details.
Still missing
- Primary case report or submitter note documenting confirmed maternity and paternity is needed.
Sources
PS3 Approved KRAS functional assay types are available in the RASopathy VCEP framework, but no variant-specific result for p.(Met170Leu) was identified in the reviewed functional materials, so PS3 cannot be applied. Details ▾Hide ▴
Rule
KRAS CSPEC PS3: Supporting for one approved assay; Moderate for two or more different approved assays.
Evidence considered
- RASopathy VCEP functional spreadsheet lists approved KRAS assay classes and PMIDs 20949621 and 23059812
- but no p.Met170Leu entry was identified.
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- Direct variant-specific functional data from an approved assay would be needed.
Sources
PS4 No case-control enrichment data or point-based affected-case evidence sufficient for PS4 was identified. Details ▾Hide ▴
Rule
KRAS CSPEC PS4 uses a point-based affected-individual framework.
Evidence considered
- ClinVar shows a VUS expert-panel record but does not provide point-based PS4 case counting in the reviewed materials.
- Population data show the variant is rare
- but rarity alone does not satisfy PS4.
Still missing
- Independent affected proband counts or formal enrichment data are needed.
Sources
PM6 No assumed or unconfirmed de novo report was identified for this variant, so PM6 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
KRAS CSPEC PM6 uses a point-based de novo framework.
Evidence considered
- No PM6-relevant de novo wording was identified in the available records.
Still missing
- Case-level reporting of de novo occurrence without full parental confirmation would be needed.
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
KRAS CSPEC PP1 uses informative meiosis thresholds.
Evidence considered
- No family segregation information was identified in the reviewed materials.
Still missing
- Family-based segregation data with informative meioses are needed.
Sources
BS2 No point-based evidence from unaffected individuals was identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
KRAS CSPEC BS2 uses a point-based unaffected-individual framework.
Evidence considered
- No BS2-relevant unaffected-individual evidence was identified in the reviewed materials.
Still missing
- Documented unaffected carrier data meeting the VCEP point system are needed.
Sources
BS4 No nonsegregation data were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
KRAS CSPEC BS4: strong with one informative meiosis showing nonsegregation.
Evidence considered
- No unaffected-carrier or nonsegregation evidence was identified in the available records.
Still missing
- Family data showing nonsegregation with the phenotype are needed.
Sources
BP2 No evidence was identified that this variant occurs with another pathogenic variant in cis or trans in a way that meets the KRAS BP2 point system. Details ▾Hide ▴
Rule
KRAS CSPEC BP2 uses a point-based framework.
Evidence considered
- No BP2-relevant phase data were identified.
Still missing
- Phase information with another relevant variant would be needed.
Sources
BP5 No alternative molecular explanation or phenotype-based negative point evidence was identified to support BP5. Details ▾Hide ▴
Rule
KRAS CSPEC BP5 uses a point-based framework.
Evidence considered
- No BP5-relevant alternative molecular cause data were identified.
Still missing
- Case-level phenotype and alternative-diagnosis data would be needed.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThis is a missense variant and does not fall into the KRAS null-variant categories used for PVS1 assessment. Details ▾Hide ▴
VCEP rule
KRAS CSPEC: PVS1 not applicable.
Evidence considered
- KRAS CSPEC marks PVS1 as not applicable.
- Generic PVS1 scaffold states this variant is not a nonsense
- frameshift
- or canonical splice variant.
Sources
PM3 VCEPPM3 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴
VCEP rule
KRAS CSPEC: PM3 not applicable.
Evidence considered
- KRAS CSPEC marks PM3 as not applicable.
Sources
PM4 N/AThis is a missense substitution and does not cause a protein length change, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 applies to protein length changes, not missense substitutions.
Evidence considered
- Variant consequence is p.(Met170Leu) missense.
Sources
PP2 VCEPPP2 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴
VCEP rule
KRAS CSPEC: PP2 not applicable.
Evidence considered
- KRAS CSPEC marks PP2 as not applicable.
Sources
PP4 VCEPPP4 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴
VCEP rule
KRAS CSPEC: PP4 not applicable.
Evidence considered
- KRAS CSPEC marks PP4 as not applicable.
Sources
PP5 VCEPPP5 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴
VCEP rule
KRAS CSPEC: PP5 not applicable.
Evidence considered
- KRAS CSPEC marks PP5 as not applicable.
Sources
BS3 VCEPBS3 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴
VCEP rule
KRAS CSPEC: BS3 not applicable.
Evidence considered
- KRAS CSPEC marks BS3 as not applicable.
Sources
BP1 N/ABP1 in this framework is used for truncating variants in genes without established loss-of-function disease correlation; this variant is missense, so BP1 is not applicable. Details ▾Hide ▴
Rule
KRAS CSPEC BP1 applies to truncating variants under specified gene-mechanism conditions.
Evidence considered
- Variant consequence is missense
- not truncating.
Sources
BP3 VCEPBP3 is not applicable in this KRAS RASopathy framework because no benign repetitive region rule is used. Details ▾Hide ▴
VCEP rule
KRAS CSPEC: BP3 not applicable.
Evidence considered
- KRAS CSPEC marks BP3 as not applicable.
Sources
BP6 VCEPBP6 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴
VCEP rule
KRAS CSPEC: BP6 not applicable.
Evidence considered
- KRAS CSPEC marks BP6 as not applicable.
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
KRAS CSPEC BP7 applies to synonymous or certain intronic/non-coding variants with no predicted splice impact.
Evidence considered
- Variant consequence is missense.
Sources
Identifiers
- Gene
- KRAS
- Transcript
- NM_001369787.1
- Coding (HGVS c.)
- NM_001369787.1:c.508A>T
- Protein (HGVS p.)
- NP_001356716.1:p.(Met170Leu)
- GRCh38
- chr12:25209854 T>A
- GRCh37
- chr12:25362788 T>A
- ClinVar
- 180859
Gene diagram
Every interpreted variant in KRAS, mapped onto the exon structure of NM_001369787.1. Select a row to find it on the plot.
KRASNM_001369787.1
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in KRAS
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
10 / 1,611,476 alleles
AF 6.21e-06 · 0 homozygotes · FAF 3.59e-06
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-06 · 10 / 1,611,476 alleles · 0 hom · FAF 3.6e-06
| Middle Eastern1 / 6,050 | 0.00017 |
| European (non-Finnish)9 / 1,178,008 | 7.6e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.20549e-06; MAF= 0.00062%, 10/1611476 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165289; MAF= 0.01653%, 1/6050 alleles, homozygotes = 0); grpmax FAF= 3.59e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.294
- BayesDel
- 0.165
How the predictions were used
BP4 SupportingComputational evidence supports BP4. REVEL is 0.294, which is below the KRAS BP4 threshold of 0.3, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04. BayesDel is 0.164958 and does not outweigh the VCEP-approved benign computational threshold. Details ▾Hide ▴
Rule
KRAS CSPEC BP4: for missense variants, REVEL at most 0.3.
Evidence considered
- REVEL score 0.294.
- SpliceAI max delta 0.04.
- BayesDel score 0.164958.
Sources
PP3 Available computational evidence does not support a damaging effect under the KRAS VCEP rule because REVEL is 0.294, which is below the PP3 threshold of 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04. Details ▾Hide ▴
Rule
KRAS CSPEC PP3: missense REVEL at least 0.7; for splicing, predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.294.
- SpliceAI max delta 0.04.
- BayesDel score 0.164958 was available as additional computational context.
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
KRAS CSPEC BP7 applies to synonymous or certain intronic/non-coding variants with no predicted splice impact.
Evidence considered
- Variant consequence is missense.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.294. BayesDel score = 0.164958.
2 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
-
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.Richards S et al. · 2015No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
10 / 1,611,476 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
3 Uncertain significance
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/643243114
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/180859/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25362788-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25209854-T-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001369787.1%3Ac.5…
- OncoKB ↗www.oncokb.org/gene/KRAS/M170L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KRAS+c.508A%3ET
- 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= 6.20549e-06; MAF= 0.00062%, 10/1611476 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165289; MAF= 0.01653%, 1/6050 alleles, homozygotes = 0); grpmax FAF= 3.59e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain significance by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 180859)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.294. BayesDel score = 0.164958.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KRAS, a GTPase which functions as an upstream regulator of the MAPK pathway, is frequently mutated in various cancer types including lung, colorectal
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.