KRAS-Related Disorders via the KRAS Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
378 KRAS$490.00 81405 Add to Order
Targeted Testing

For ordering sequencing of targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

This test will detect causative KRAS mutations in less than 5% of NS patients (Allanson and Roberts 2011) and in ~ 2-3 % of CFCS patients (Rauen 2010).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 KRAS$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Features

Noonan Syndrome (NS, OMIM 163950) is a relatively common developmental disorder that is characterized by dysmorphic facial features, growth and congenital heart defects, and musculoskeletal abnormalities.  Cardiac abnormalities are found in up to 80% of patients and include pulmonary valve stenosis, atrial septal defect, atrioventricular canal defect, and hypertrophic cardiomyopathy.  Musculoskeletal abnormalities include short stature, chest deformity with sunken or raised sternum, and short webbed neck.  Several additional abnormalities have been described and include renal, genital, hematological, neurologic,  cognitive, behavioral, gastrointestinal, dental, and lymphatic findings.  Intelligence is usually normal; however, learning disabilities may be present.  NS is characterized by an extensive clinical heterogeneity, even among members of the same family.  Diagnosis is often made in infancy or early childhood.  Symptoms often change and lessen with advancing age.  Infants with NS are at risk of developing juvenile myelomonocytic leukemia (JMML OMIM 607785).  The prevalence of NS is estimated at 1 in 1000 to 1 in 2,500 births worldwide (Allanson et al. Am J Med Genet 21:507-514, 1985; Romano et al. Pediatrics 126:746-759, 2010).

Cardio-Facio-Cutaneous Syndrome (CFCS, OMIM 115150) is a rare developmental disorder characterized by distinctive facial appearance; congenital cardiac and ectodermal abnormalities; postnatal growth failure; feeding difficulties with failure to thrive and neurological findings.  Facial features include high forehead, short, upturned nose with a low nasal bridge, prominent external ears that are posteriorly angulated and ocular hypertelorism.  The most common cardiac abnormalities include pulmonic stenosis and atrial septal defects.  Ectodermal abnormalities are heterogeneous in features and severity.  They include café au lait spots, erythema, keratosis, ichthyosis, eczema, sparse and brittle hair, and nail dystrophy.  The neurological findings include seizures, hypotonia,  macrocephaly and various degrees of mental and cognitive delay (Reynolds et al. Am J Med Genet 25:413-427, 1986).


NS is caused by gain of function mutations in various genes within the RAS/MAPK pathway, including KRAS.  To date, seven RAS/MAPK genes (PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF and NRAS) have been involved in patients with NS.  KRAS mutations account for less than 5% of all cases genotyped (Schubbert et al. Nat Genet 38:331-336, 2006).  To date, thirteen mutations, all missense, were reported.  Although de novo KRAS mutations are found in most NS patients, familial cases have been reported.  In these families, NS is inherited as an autosomal dominant trait. 

Genotype-phenotype correlations are slowly being made.  Mild to moderate mental retardation appears to be more common in NS patients with KRAS mutations compared to other NS patients (Zenker et al. J Med Genet 44:131-135, 2007; Allanson et al. J Med Genet 24:9-13, 1987).  Craniosynostosis has been documented in a few unrelated NS patients with KRAS mutations (Kratz et al. Am J Med Genet A 149A:1036-40, 2009; Brasil et al. Am J Med Genet A 158A:1178-1184, 2012).  

CFCS is caused by mutations in four genes within the RAS/MAPK pathway: BRAF, MAP2K1, MAP2K1 and KRAS (Rodriguez-Viciana et al. Science 311:1287-1290, 2006; Niihori et al. Nat Genet 38:294-296, 2006).  To date, only four  KRAS mutations were detected in patients with CFCS.  All four mutations are missense, and account for a small fraction of all cases genotyped.  All CFCS with KRAS mutations are sporadic resulting from de novo dominant KRAS mutations.  To date, no mosaicism in the KRAS gene has been reported in CFCS patients (Rauen, GeneReviews, 2010).

Somatic KRAS mutations have been implicated in several human cancers, including juvenile myelomonocytic leukemia (JMML OMIM 607785) (Reimann et al. Leukemia 20:1637-1638, 2006) and colon cancer (Edkins et al. Cancer Biol Ther 5:928-932, 2006).

Testing Strategy

This test involves bidirectional DNA sequencing of all coding exons of the KRAS gene. The full coding region of each exon plus ~10 bp of flanking non-coding DNA on either side are sequenced. We will also sequence and single exon (Test #100) in family members of patients with a known mutation or to confirm research results.

Indications for Test

All NS and CFC Syndrome patients that are negative for mutations in the primary genes (PTPN11 and BRAF) are candidates for this test.


Official Gene Symbol OMIM ID
KRAS 190070
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Genetic Counselors
  • Allanson et al. Noonan syndrome. J Med Genet 24:9-13, 1987 PubMed ID: 3543368
  • Allanson JE, Hall JG, Hughes HE, Preus M, Witt RD. 1985. Noonan syndrome: the changing phenotype. Am. J. Med. Genet. 21: 507-514. PubMed ID: 4025385
  • Brasil et al. KRAS gene mutations in Noonan syndrome familial cases cluster in the vicinity of the switch II region of the G-domain: report of another family with metopic craniosynostosis.  Am J Med Genet A 158A:1178-1184, 2012 PubMed ID: 22488932
  • Edkins S, O’Meara S, Parker A, Stevens C, Reis M, Jones S, Greenman C, Davies H, Dalgliesh G, Forbes S. 2006. Brief Communication Recurrent KRAS Codon 146 Mutations in Human Colorectal Cancer. Cancer biology & therapy 5: 928–932. PubMed ID: 16969076
  • Kratz et al. Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations. Am J Med Genet A 149A:1036-40, 2009 PubMed ID: 19396835
  • Niihori T, Aoki Y, Narumi Y, Neri G, Cavé H, Verloes A, Okamoto N, Hennekam RCM, Gillessen-Kaesbach G, Wieczorek D, Kavamura MI, Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G, Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, Kure S, Matsubara Y. 2006. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat. Genet. 38: 294–296. PubMed ID: 16474404
  • Rauen KA. 2010. Cardiofaciocutaneous Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301365
  • Reimann C, Arola M, Bierings M, Karow A, Heuvel-Eibrink MM van den, Hasle H, Niemeyer CM, Kratz CP. 2006. A novel somatic K-Ras mutation in juvenile myelomonocytic leukemia. Leukemia 20: 1637–1638. PubMed ID: 16826224
  • Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, Opitz JM. 1986. New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement--the CFC syndrome. Am. J. Med. Genet. 25: 413–427. PubMed ID: 3789005
  • Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS, McCormick F, Rauen KA.. 2006. Germline Mutations in Genes Within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome. Science 311: 1287–1290. PubMed ID: 16439621
  • Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. 2010. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 126: 746-759. PubMed ID: 20876176
  • Schubbert, S., (2006). "Germline KRAS mutations cause Noonan syndrome." Nat Genet 38(3): 331-6. PubMed ID: 16474405
  • Zenker, M., (2007). "Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations." J Med Genet 44(2): 131-5. PubMed ID: 17056636
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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