About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.519T>C, p.(Asp173=)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign 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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BA1Stand alone
BA1 · stand alone
This synonymous KRAS variant is present at a population frequency far above the benign stand-alone threshold. In gnomAD, the allele frequency is 19.06% in v2.1 and 20.60% in v4.1, which is well above the KRAS RASopathy VCEP BA1 threshold of 0.05%.
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.
Recorded classification: Benign
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 Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP6 supporting benign; maps to Benign.
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
331,554 / 1,609,518 alleles
gnomAD v4.1: 331,554 / 1,609,518 alleles. Recorded AF 0.205996. Recorded homozygote count 34745.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.190556; MAF= 19.05559%, 53595/281256 alleles, homozygotes = 5310) and has highest observed frequency in the European (non-Finnish) population (AF= 0.221247; MAF= 22.12469%, 28382/128282 alleles, homozygotes = 3073); grpmax FAF= 0.220075.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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: 2 met · 4 not met · 10 not assessed · 12 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.519T>C (p.Asp173=; p.D173=) variant has been reported in ClinVar as Benign, including by the ClinGen RASopathy Variant Curation Expert Panel.
This variant is common in population databases, with an allele frequency of 19.06% in gnomAD v2.1 and 20.60% in gnomAD v4.1, which is far above the KRAS RASopathy VCEP BA1 benign threshold of 0.05%.
In silico splicing analysis predicts no significant splice impact, with a SpliceAI maximum delta score of 0.10.
No criteria match.
Met · 2
BA1 Stand aloneThis synonymous KRAS variant is present at a population frequency far above the benign stand-alone threshold. In gnomAD, the allele frequency is 19.06% in v2.1 and 20.60% in v4.1, which is well above the KRAS RASopathy VCEP BA1 threshold of 0.05%. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.05%.
Evidence considered
- gnomAD v2.1 total AF 0.190556 (53
- 595/281
- 256 alleles
- 5
- 310 homozygotes)
- gnomAD v4.1 total AF 0.205996 (331
- 554/1
- 609
- 518 alleles
- 34
- 745 homozygotes)
- KRAS RASopathy VCEP BA1 threshold: filtering allele frequency >=0.05%
Sources
Not met · 4 · evaluated, threshold not reached
PS4 Available evidence does not support enrichment in affected individuals. This variant is common in population databases, so the KRAS RASopathy VCEP PM2 absence-from-controls requirement that precedes PS4 is not met. Details ▾Hide ▴
Rule
Strong >=5 points; Moderate >=3 points; Supporting >=1 point.
Evidence considered
- gnomAD v2.1 AF 0.190556
- gnomAD v4.1 AF 0.205996
- KRAS RASopathy VCEP PS4 is point based and depends on rarity context
Sources
PM1 This variant does not fall within the KRAS RASopathy VCEP PM1 functional domain ranges of amino acids 10-17, 25-40, 57-64, or 145-156. The synonymous residue Asp173 is outside these specified domains, and no hotspot evidence supporting codon 173 was identified. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains: P-loop 10-17, SW1 25-40, SW2 57-64, SAK 145-156.
Evidence considered
- PM1 domains in KRAS VCEP: 10-17
- 25-40
- 57-64
- 145-156
- Protein consequence p.(Asp173=) / p.(D173=)
- Cancer Hotspots review did not identify a statistically significant hotspot at D173
Sources
PM2 This variant is not absent from controls. In gnomAD, the allele frequency is 19.06% in v2.1 and 20.60% in v4.1, so the KRAS RASopathy VCEP PM2 absence-from-controls requirement is not met. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1 AF 0.190556
- gnomAD v4.1 AF 0.205996
Sources
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.10, which does not support an abnormal splicing outcome consistent with disease mechanism; REVEL and BayesDel scores were not available. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI DS_AG 0.00
- DS_AL 0.00
- DS_DG 0.10
- DS_DL 0.00
- max delta 0.10
- REVEL not found
- BayesDel not found
Sources
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
Very Strong 4 points; Strong 2 points; Moderate 1 point.
Evidence considered
- KRAS RASopathy VCEP PS2 is point based
Still missing
- Variant-specific maternity and paternity-confirmed de novo data were not identified.
Sources
PS3 No approved variant-specific functional assay evidence was identified for this synonymous KRAS variant. Details ▾Hide ▴
Rule
Moderate with two or more different approved assays; Supporting with one approved assay.
Evidence considered
- RASopathy VCEP approved functional studies resource reviewed
- OncoKB entry was not variant specific and listed unknown oncogenic effect
Still missing
- Variant-specific approved functional assay data were not identified.
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
Strong 2 points; Moderate 1 point; Supporting 0.5 point.
Evidence considered
- KRAS RASopathy VCEP PM6 is point based
Still missing
- Variant-specific apparent de novo data were not identified.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
Supporting >=3 informative meioses; Moderate >=5; Strong >=7.
Evidence considered
- KRAS RASopathy VCEP PP1 requires >=3 informative meioses for supporting strength
Still missing
- Informative meiosis data were not identified.
Sources
BS1 Population frequency also exceeds the BS1 threshold, but BA1 is already met and is the more appropriate population rule for this variant. Separate BS1 application would not add clinically meaningful evidence beyond BA1. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.025%.
Evidence considered
- gnomAD v2.1 total AF 0.190556
- gnomAD v4.1 total AF 0.205996
- KRAS RASopathy VCEP BS1 threshold: filtering allele frequency >=0.025%
Sources
BS2 This variant is common in population databases, including many homozygotes, but no phenotype-linked adult observation data were identified to assign the KRAS RASopathy VCEP BS2 point-based rule directly. Details ▾Hide ▴
Rule
Point-based benign evidence from observations in unaffected individuals.
Evidence considered
- gnomAD v2.1 includes 5
- 310 homozygotes
- gnomAD v4.1 includes 34
- 745 homozygotes
Still missing
- Phenotyped unaffected carrier data were not identified.
Sources
BS4 No family data showing lack of segregation were identified for this variant. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- KRAS RASopathy VCEP BS4 requires informative meiosis data
Still missing
- Pedigree-level non-segregation data were not identified.
Sources
BP2 No phase data or point-based evidence for occurrence with another causative variant were identified for this variant. Details ▾Hide ▴
Rule
Point-based benign evidence.
Evidence considered
- KRAS RASopathy VCEP BP2 is point based
Still missing
- Phase information and alternate-cause point data were not identified.
Sources
BP5 No evidence was identified for an alternative molecular explanation or phenotype inconsistency meeting the KRAS RASopathy VCEP point-based BP5 rule. Details ▾Hide ▴
Rule
Point-based benign evidence for alternate molecular cause or phenotype inconsistency.
Evidence considered
- KRAS RASopathy VCEP BP5 is point based
Still missing
- Variant-specific alternate-diagnosis evidence was not identified.
Sources
BP7 This is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.10. However, the KRAS RASopathy VCEP BP7 rule also requires that the nucleotide not be highly conserved, and no conservation evidence was identified here. Details ▾Hide ▴
Rule
A synonymous variant with no predicted splice impact and a nucleotide that is not highly conserved.
Evidence considered
- Protein consequence p.(Asp173=) / p.(D173=)
- SpliceAI max delta score 0.10 with no significant predicted splice impact
Still missing
- Nucleotide conservation evidence was not identified.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThe KRAS RASopathy VCEP marks PVS1 as not applicable for this framework, and this variant is a synonymous substitution rather than a nonsense, frameshift, or canonical +/-1,2 splice variant. Details ▾Hide ▴
Evidence considered
- KRAS RASopathy VCEP applicability table
- Variant-level PVS1 assessment: not a default null-variant bucket
- Canonical splice consensus: false
Sources
PS1 N/AThis variant is synonymous and does not create an amino acid change, so the same-amino-acid pathogenic substitution rule does not apply. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- Protein consequence p.(Asp173=) / p.(D173=)
Sources
PM3 N/AThe KRAS RASopathy VCEP marks PM3 as not applicable. Details ▾Hide ▴
PM4 N/AThis variant is a synonymous single-nucleotide substitution and does not produce a protein length change or in-frame insertion/deletion. Details ▾Hide ▴
Rule
Moderate for protein length changes or in-frame indels as specified.
Evidence considered
- Protein consequence p.(Asp173=) / p.(D173=)
Sources
PM5 N/AThis variant is synonymous and does not create a novel amino acid substitution at codon 173, so the same-codon different-pathogenic-missense rule does not apply. Details ▾Hide ▴
Rule
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Evidence considered
- Protein consequence p.(Asp173=) / p.(D173=)
Sources
PP2 N/AThe KRAS RASopathy VCEP marks PP2 as not applicable. Details ▾Hide ▴
PP4 N/AThe KRAS RASopathy VCEP marks PP4 as not applicable. Details ▾Hide ▴
PP5 N/AThe KRAS RASopathy VCEP marks PP5 as not applicable. Details ▾Hide ▴
BS3 N/AThe KRAS RASopathy VCEP marks BS3 as not applicable. Details ▾Hide ▴
BP1 N/AThis rule is reserved in the KRAS RASopathy specification for truncating variants in genes without an established loss-of-function disease correlation. This variant is synonymous and is not a truncating variant. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established LOF correlation to disease.
Evidence considered
- Protein consequence p.(Asp173=) / p.(D173=)
- KRAS RASopathy VCEP BP1 instructions
Sources
BP3 N/AThe KRAS RASopathy VCEP marks BP3 as not applicable because no known benign repetitive regions are defined for this context. Details ▾Hide ▴
BP4 N/AIn the KRAS RASopathy specification, BP4 is defined for missense variants with REVEL <=0.3. This variant is synonymous, not missense, and no REVEL or BayesDel score was available. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3.
Evidence considered
- Protein consequence p.(Asp173=) / p.(D173=)
- REVEL not found
- BayesDel not found
Sources
Identifiers
- Gene
- KRAS
- Transcript
- NM_001369787.1
- Coding (HGVS c.)
- NM_001369787.1:c.519T>C
- Protein (HGVS p.)
- NP_001356716.1:p.(Asp173=)
- GRCh38
- chr12:25209843 A>G
- GRCh37
- chr12:25362777 A>G
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
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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
331,554 / 1,609,518 alleles
AF 0.206 · 34745 homozygotes · FAF 0.227
gnomAD v2.1
53,595 / 281,256 alleles
AF 0.191 · 5310 homozygotes · FAF 0.22
By genetic ancestry
gnomAD v4.1
AF 0.21 · 331554 / 1,609,518 alleles · 34745 hom · FAF 0.23
| Amish360 / 910 | 0.472 hom |
| Middle Eastern1429 / 6,034 | 0.24188 hom |
| European (non-Finnish)255635 / 1,176,612 | 0.2227665 hom |
| Remaining individuals12556 / 62,338 | 0.21264 hom |
| South Asian17509 / 90,800 | 0.191865 hom |
| Admixed American10788 / 59,890 | 0.18998 hom |
| African/African American13176 / 74,860 | 0.181190 hom |
| Ashkenazi Jewish4811 / 29,538 | 0.16382 hom |
| European (Finnish)10201 / 63,850 | 0.16830 hom |
| East Asian5089 / 44,686 | 0.11291 hom |
gnomAD v2.1
AF 0.19 · 53595 / 281,256 alleles · 5310 hom · FAF 0.22
| European (non-Finnish)28382 / 128,282 | 0.223073 hom |
| Remaining individuals1470 / 7,172 | 0.2144 hom |
| South Asian5808 / 30,436 | 0.19597 hom |
| African/African American4373 / 24,844 | 0.18378 hom |
| Admixed American6048 / 35,250 | 0.17554 hom |
| Ashkenazi Jewish1696 / 10,336 | 0.16129 hom |
| European (Finnish)3924 / 25,032 | 0.16341 hom |
| East Asian1894 / 19,904 | 0.09594 hom |
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.205996; MAF= 20.59958%, 331554/1609518 alleles, homozygotes = 34745) and has highest observed frequency in the Amish population (AF= 0.395604; MAF= 39.56044%, 360/910 alleles, homozygotes = 72); grpmax FAF= 0.226615.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.190556; MAF= 19.05559%, 53595/281256 alleles, homozygotes = 5310) and has highest observed frequency in the European (non-Finnish) population (AF= 0.221247; MAF= 22.12469%, 28382/128282 alleles, homozygotes = 3073); grpmax FAF= 0.220075.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.10, which does not support an abnormal splicing outcome consistent with disease mechanism; REVEL and BayesDel scores were not available. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI DS_AG 0.00
- DS_AL 0.00
- DS_DG 0.10
- DS_DL 0.00
- max delta 0.10
- REVEL not found
- BayesDel not found
Sources
BP7 This is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.10. However, the KRAS RASopathy VCEP BP7 rule also requires that the nucleotide not be highly conserved, and no conservation evidence was identified here. Details ▾Hide ▴
Rule
A synonymous variant with no predicted splice impact and a nucleotide that is not highly conserved.
Evidence considered
- Protein consequence p.(Asp173=) / p.(D173=)
- SpliceAI max delta score 0.10 with no significant predicted splice impact
Still missing
- Nucleotide conservation evidence was not identified.
Sources
BP4 N/AIn the KRAS RASopathy specification, BP4 is defined for missense variants with REVEL <=0.3. This variant is synonymous, not missense, and no REVEL or BayesDel score was available. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3.
Evidence considered
- Protein consequence p.(Asp173=) / p.(D173=)
- REVEL not found
- BayesDel not found
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
331,554 / 1,609,518 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/41449/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25362777-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25209843-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001369787.1%3Ac.5…
- OncoKB ↗www.oncokb.org/gene/KRAS/D173=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KRAS+c.519T%3EC
- 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= 0.205996; MAF= 20.59958%, 331554/1609518 alleles, homozygotes = 34745) and has highest observed frequency in the Amish population (AF= 0.395604; MAF= 39.56044%, 360/910 alleles, homozygotes = 72); grpmax FAF= 0.226615.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.190556; MAF= 19.05559%, 53595/281256 alleles, homozygotes = 5310) and has highest observed frequency in the European (non-Finnish) population (AF= 0.221247; MAF= 22.12469%, 28382/128282 alleles, homozygotes = 3073); grpmax FAF= 0.220075.
ClinVar
This variant has been reported in ClinVar as Benign (13 clinical laboratories) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.