About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.178G>C, p.(Gly60Arg)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 6
Benign evidence criteria: 0
Pathogenic criteria applied · 6
PS3Moderate
PS3 · moderate
In published functional studies, this variant increased the active GTP-bound KRAS fraction, showed marked GAP resistance, and increased downstream MEK and ERK phosphorylation relative to wild type, consistent with an activating effect. The RASopathy VCEP approved functional-study resource lists this variant as a pathogenic control in multiple approved assay types, which supports PS3 at moderate strength because two or more different approved assays were available.
PM1Moderate
PM1 · moderate
This missense variant affects KRAS residue 60, which lies within the Switch II region (amino acids 57-64), a critical and well-established functional domain specified for PM1 in the KRAS RASopathy framework.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the KRAS RASopathy PM2 requirement for absence from population controls.
PM5Moderate
PM5 · moderate
Different missense substitutions at KRAS codon 60 have been reported as pathogenic or likely pathogenic in ClinVar, including p.Gly60Val and p.Gly60Ser, which supports the classic same-residue PM5 rule at moderate strength for this novel amino acid change.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious missense effect. The REVEL score is 0.938, which is above the KRAS RASopathy PP3 threshold of 0.7, and BayesDel is also positive at 0.539464. SpliceAI shows a possible splice effect with a max delta score of 0.25, but no RNA evidence was identified to establish a splice-based mechanism.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule14 (2 Pathogenic.Moderate + Pathogenic.Supporting >=2) with applied criteria: PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting, PS3 moderate; maps to Likely Pathogenic.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.250 maximum delta
Recorded SpliceAI maximum delta score: 0.250. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
8 reported laboratory submissions
8 Pathogenic.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55690921, n = 1 times).
Cancer Hotspots
This variant lies 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: 6 met · 4 not met · 8 not assessed · 10 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.178G>C (p.Gly60Arg) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar, where it is classified as Pathogenic including review by the ClinGen RASopathy expert panel.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.
In a published functional study, this variant increased the active GTP-bound KRAS fraction, showed marked GAP resistance, and increased downstream MEK and ERK signaling relative to wild type, consistent with an activating effect; the RASopathy VCEP approved functional-study resource also supports use of multiple approved assay types for this variant.
Computational evidence supports a damaging missense effect, with REVEL 0.938 above the KRAS PP3 threshold of 0.7 and a positive BayesDel score of 0.539464; SpliceAI shows a possible splice effect with a max delta score of 0.25, but no RNA evidence was identified.
No criteria match.
Met · 6
PS3 ModerateIn published functional studies, this variant increased the active GTP-bound KRAS fraction, showed marked GAP resistance, and increased downstream MEK and ERK phosphorylation relative to wild type, consistent with an activating effect. The RASopathy VCEP approved functional-study resource lists this variant as a pathogenic control in multiple approved assay types, which supports PS3 at moderate strength because two or more different approved assays were available. Details ▾Hide ▴
Rule
Two or more different approved assays.
Evidence considered
- PMID:20949621 reported increased GTP-bound KRAS
- GAP resistance
- and increased downstream signaling for G60R.
- The VCEP approved functional-study spreadsheet lists G60R as a pathogenic control in approved RAS activation
- MEK activation
- and ERK activation assays.
- KRAS RASopathy PS3 allows moderate strength for two or more different approved assays.
Sources
PM1 ModerateThis missense variant affects KRAS residue 60, which lies within the Switch II region (amino acids 57-64), a critical and well-established functional domain specified for PM1 in the KRAS RASopathy framework. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains: P-loop (AA 10-17), SW1 (AA 25-40), SW2 (AA 57-64), SAK (AA 145-156).
Evidence considered
- Residue 60 falls within KRAS Switch II (AA 57-64).
- KRAS RASopathy PM1 permits moderate strength for variants in Switch II.
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the KRAS RASopathy PM2 requirement for absence from population controls. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
PM5 ModerateDifferent missense substitutions at KRAS codon 60 have been reported as pathogenic or likely pathogenic in ClinVar, including p.Gly60Val and p.Gly60Ser, which supports the classic same-residue PM5 rule at moderate strength for this novel amino acid change. Details ▾Hide ▴
Rule
1 pathogenic/likely pathogenic residue change at the same codon.
Evidence considered
- ClinVar same-codon comparators identified by tool review included KRAS p.Gly60Val (Pathogenic/Likely pathogenic
- multiple submitters
- no conflicts) and KRAS p.Gly60Ser (Pathogenic
- no conflicts).
- KRAS RASopathy PM5 allows moderate strength for one pathogenic or likely pathogenic residue change at the same codon.
Still missing
- A same-residue expert-panel comparator was not identified in the retrieved materials
- same-residue support came from ClinVar multiple-submitter assertions.
Sources
PP3 SupportingComputational evidence supports a deleterious missense effect. The REVEL score is 0.938, which is above the KRAS RASopathy PP3 threshold of 0.7, and BayesDel is also positive at 0.539464. SpliceAI shows a possible splice effect with a max delta score of 0.25, but no RNA evidence was identified to establish a splice-based mechanism. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.938.
- BayesDel score 0.539464.
- SpliceAI max delta score 0.25.
- KRAS RASopathy PP3 threshold is REVEL >=0.7 for missense variants.
Sources
Not met · 4 · evaluated, threshold not reached
PS1 No different nucleotide change producing the same amino acid substitution with established pathogenic classification was identified for KRAS p.Gly60Arg, so PS1 is not met. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar review identified the exact variant NM_004985.5(KRAS):c.178G>C (p.Gly60Arg).
- No alternate nucleotide encoding the same amino acid substitution was confirmed.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the population frequency is below the KRAS RASopathy BA1 threshold of 0.05% and BA1 is not met. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.05%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- KRAS RASopathy BA1 threshold is filtering allele frequency >=0.05%.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the population frequency is below the KRAS RASopathy BS1 threshold of 0.025% and BS1 is not met. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.025%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- KRAS RASopathy BS1 threshold is filtering allele frequency >=0.025%.
Sources
BP4 Available computational evidence does not support a benign missense effect. The REVEL score is 0.938, which is above the KRAS RASopathy BP4 benign threshold of 0.3, and BayesDel is also positive at 0.539464. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3.
Evidence considered
- REVEL score 0.938.
- BayesDel score 0.539464.
- KRAS RASopathy BP4 threshold is REVEL <=0.3 for missense variants.
Sources
Not assessed · 8 · no assessment recorded
PS2 Published affected-case evidence exists for this variant, but no directly confirmed de novo occurrence with sufficient parental confirmation and phenotype detail was verified from the reviewed sources, so PS2 was not assessed. Details ▾Hide ▴
Rule
De novo criterion scored by points under the RASopathy framework.
Evidence considered
- This variant has published case reports and ClinVar submissions.
- No reviewed source provided a confirmed PS2 point assignment.
Still missing
- No confirmed de novo case with documented maternity and paternity confirmation was verified.
- Point total for the RASopathy de novo framework was not established.
Sources
PS4 This variant has been reported in affected individuals and is classified as pathogenic by the ClinGen RASopathy expert panel in ClinVar, but the reviewed evidence did not establish the point total required by the KRAS RASopathy PS4 framework, so PS4 was not assessed. Details ▾Hide ▴
Rule
Supporting >=1 point; Moderate >=3 points; Strong >=5 points.
Evidence considered
- ClinVar lists an expert-panel pathogenic classification for this variant.
- Published case reports exist
- but the PS4 point total was not calculated from the reviewed evidence.
Still missing
- Independent affected-case count was not resolved.
- Phenotype-based PS4 point total was not established.
Sources
PM6 Affected-case reports were identified in the literature and ClinVar, but no directly verified assumed de novo occurrence suitable for PM6 point assignment was confirmed from the reviewed evidence. Details ▾Hide ▴
Rule
Assumed de novo, scored by points under the RASopathy framework.
Evidence considered
- Case reports and ClinVar submissions exist for this variant.
- No reviewed source provided a confirmed PM6 point assignment.
Still missing
- No assumed de novo case with sufficient inheritance detail was confirmed.
- Independent occurrence count was not resolved.
Sources
PP1 No informative familial segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
Supporting >=3 informative meioses; Moderate >=5; Strong >=7.
Evidence considered
- KRAS RASopathy PP1 requires informative meioses.
Still missing
- No multiple affected relatives with confirmed segregation were identified.
Sources
BS2 No confirmed unaffected adult carriers or point-based BS2 evidence were identified, so BS2 was not assessed. Details ▾Hide ▴
Rule
-4 points for strong or -1 point for supporting.
Evidence considered
- KRAS RASopathy BS2 uses point-based scoring from unaffected individuals.
Still missing
- No unaffected carrier data were identified.
- No point-based BS2 calculation was available.
Sources
BS4 No informative non-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- KRAS RASopathy BS4 requires informative non-segregation evidence.
Still missing
- No tested unaffected carriers were identified.
- No affected non-carriers were identified.
Sources
BP2 No phased second pathogenic variant in KRAS and no point-based evidence for an alternative molecular cause in the same gene were identified, so BP2 was not assessed. Details ▾Hide ▴
Rule
Point-based scoring for an alternative molecular cause in the same gene.
Evidence considered
- KRAS RASopathy BP2 uses point-based scoring tied to an alternative molecular cause in the same gene.
Still missing
- No segregation or phase data were identified.
- No alternate same-gene pathogenic variant context was identified.
Sources
BP5 No confirmed alternative molecular diagnosis or phenotype-based negative point evidence was identified, so BP5 was not assessed. Details ▾Hide ▴
Rule
Point-based scoring for an alternative molecular cause or phenotype inconsistency.
Evidence considered
- KRAS RASopathy BP5 is a point-based criterion requiring an alternative molecular explanation or phenotype mismatch.
Still missing
- No alternate causative variant was identified.
- No phenotype-specific negative point assignment was available.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThis is a missense variant and does not fall into a null-variant category. The KRAS RASopathy framework lists PVS1 as not applicable for this case context, and the generic PVS1 scaffold also indicates that this variant is not a nonsense, frameshift, or canonical splice-site change. Details ▾Hide ▴
Evidence considered
- KRAS criteria list PVS1 as not applicable.
- Generic PVS1 scaffold classifies this variant outside the default null-variant buckets.
Sources
cspec ↗pvs1_variant_assessment
PM3 VCEPPM3 is not applicable in the KRAS RASopathy framework. Details ▾Hide ▴
PM4 N/AThis is not an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 does not apply. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Variant is a missense substitution.
Sources
PP2 VCEPPP2 is not applicable in the KRAS RASopathy framework. Details ▾Hide ▴
PP4 VCEPPP4 is not applicable in the KRAS RASopathy framework. Details ▾Hide ▴
BS3 VCEPBS3 is not applicable in the KRAS RASopathy framework, and the available functional studies support abnormal rather than normal KRAS activity. Details ▾Hide ▴
Evidence considered
- KRAS criteria list BS3 as not applicable.
- Published functional data show abnormal KRAS behavior for this variant.
Sources
BP1 N/AThis is a missense variant, not a truncating variant, so the KRAS RASopathy BP1 rule for truncating variants in a gain-of-function disease context does not apply. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established loss-of-function correlation to disease.
Evidence considered
- Variant is NP_004976.2:p.(Gly60Arg)
- a missense change.
- KRAS BP1 is specified for truncating variants in this framework.
Sources
BP3 VCEPBP3 is not applicable in the KRAS RASopathy framework because there are no established benign repetitive regions for this rule in these genes. Details ▾Hide ▴
BP6 VCEPBP6 is not used in this KRAS RASopathy framework. Details ▾Hide ▴
BP7 N/AThis is a missense variant, not a synonymous or noncoding change, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or eligible intronic/non-coding variant with no predicted splice impact and low conservation concern.
Evidence considered
- Variant is NP_004976.2:p.(Gly60Arg)
- a missense change.
Sources
Identifiers
- Gene
- KRAS
- Transcript
- NM_004985.4
- Coding (HGVS c.)
- NM_004985.4:c.178G>C
- Protein (HGVS p.)
- NP_004976.2:p.(Gly60Arg)
- GRCh38
- chr12:25227346 C>G
- GRCh37
- chr12:25380280 C>G
- ClinVar
- 12586
- COSMIC
- COSV55690921
Gene diagram
Every interpreted variant in KRAS, mapped onto the exon structure of NM_004985.4. Select a row to find it on the plot.
KRASNM_004985.4
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.938
- BayesDel
- 0.539
How the predictions were used
PP3 SupportingComputational evidence supports a deleterious missense effect. The REVEL score is 0.938, which is above the KRAS RASopathy PP3 threshold of 0.7, and BayesDel is also positive at 0.539464. SpliceAI shows a possible splice effect with a max delta score of 0.25, but no RNA evidence was identified to establish a splice-based mechanism. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.938.
- BayesDel score 0.539464.
- SpliceAI max delta score 0.25.
- KRAS RASopathy PP3 threshold is REVEL >=0.7 for missense variants.
Sources
BP4 Available computational evidence does not support a benign missense effect. The REVEL score is 0.938, which is above the KRAS RASopathy BP4 benign threshold of 0.3, and BayesDel is also positive at 0.539464. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3.
Evidence considered
- REVEL score 0.938.
- BayesDel score 0.539464.
- KRAS RASopathy BP4 threshold is REVEL <=0.3 for missense variants.
Sources
BP7 N/AThis is a missense variant, not a synonymous or noncoding change, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or eligible intronic/non-coding variant with no predicted splice impact and low conservation concern.
Evidence considered
- Variant is NP_004976.2:p.(Gly60Arg)
- a missense change.
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.25). REVEL score = 0.938. BayesDel score = 0.539464.
13 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 20949621 ↗Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders.No paper-specific finding is recorded.
-
PMID 24030381 ↗Clinical and biological implications of driver mutations in myelodysplastic syndromes.No paper-specific finding is recorded.
-
PMID 19396835 ↗Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations.Kratz CP et al. · 2009No paper-specific finding is recorded.
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PMID 23652378 ↗A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.No paper-specific finding is recorded.
-
PMID 24033266 ↗A systematic approach to assessing the clinical significance of genetic variants.No paper-specific finding is recorded.
-
PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.No paper-specific finding is recorded.
-
PMID 25730230 ↗Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.No paper-specific finding is recorded.
-
PMID 22947299 ↗Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.No paper-specific finding is recorded.
-
PMID 23037933 ↗Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.No paper-specific finding is recorded.
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PMID 23881473 ↗Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.No paper-specific finding is recorded.
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PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.No paper-specific finding is recorded.
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PMID 25173338 ↗2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.250
Open source ↗
ClinVar
8 Pathogenic
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/12586/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25380280-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25227346-C-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004985.4%3Ac.178G…
- OncoKB ↗www.oncokb.org/gene/KRAS/G60R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108072561
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 12586)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.25). REVEL score = 0.938. BayesDel score = 0.539464.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55690921, n = 1 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.