• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The EGFR gene is associated with autosomal dominant predisposition to lung cancer (PMID: 16258541, 24736066, 24736080, 21252721, 23380224, 25176975, 18355544, 23358982).

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Invitae tests that include this gene:

The EGFR gene encodes epidermal growth factor receptor, a protein kinase that binds epidermal growth factor and is involved in cell proliferation, differentiation, motility, and survival (PMID: 7937865, 21575252).

EGFR c.2369C>T (p.Thr790Met)
MedGen UID: 475825

Clinical condition
The EGFR c.2369C>T (p.Thr790Met) variant, also known as T790M, has been identified as a rare cause of hereditary predisposition to non-small cell lung cancer (PMID: 16258541, 24736066, 24736080, 21252721). The risk for carriers of this variant to develop non-small cell lung cancer is estimated to be 23%, although data are limited by the very small number of reported cases (PMID: 24736066). The average age at diagnosis is 63 years, with a range of ages similar to diagnoses of BRCA1 carriers (PMID: 24736066). It is estimated that 1% of non-small cell lung cancer patients and less than 1 in 7500 individuals in the general population are carriers of this hereditary variant (PMID: 24736066).

Although based on small studies, the T790M variant in EGFR appears to confer a higher risk of lung cancer in non-smokers (31%) than in smokers (15%; PMID: 24736066). The molecular pathways to the development of non-hereditary lung adenocarcinoma in smokers versus non-smokers tend to be different: pathogenic variants in the KRAS gene are the most common driver in smokers, while in non-smokers it appears to be driven by deleterious variants in EGFR (PMID: 15741570). These pathways in lung cancer development seem to be mutually exclusive; (PMID: 24736066).

EGFR T790M is most commonly tested for as a somatic variant in the lung tumor tissue of patients with a cancer diagnosis. It has been hypothesized that the T790M mutation is growth promoting by increasing kinase activity and downstream signaling (PMID: 17510392). Activating EGFR mutations typically predict response to tyrosine kinase inhibitors such as gefitinib. However, the T790M mutation confers resistance to these treatments, and, if present, is typically acquired over the course of treatment. Identification of the EGFR T790M variant prior to treatment may be suggestive of its presence in the germline (PMID: 22588155).

Gene information
EGFR encodes the epidermal growth factor receptor, a transmembrane receptor tyrosine kinase. Binding of EGF to EGFR leads to receptor dimerization and auto-/trans-phosphorylation of intracellular tyrosine residues, which activates signaling pathways. Activating mutations leading to enhanced autophosphorylation in the absence of ligand may be associated with a proliferative advantage (PMID: 7937865, 21575252).

Increased risk for lung cancer associated with the EGFR c.2369C>T (p.Thr790Met) variant is inherited in an autosomal dominant manner. This means that an individual with this variant has a 50% chance of passing it on to their offspring.

While there are no established screening or surveillance guidelines for individuals with the T790M variant, regular CT scans for early detection of lung cancer in carriers have been suggested (PMID: 24736066, 24736080). Ongoing studies looking at patients and relatives with this variant may further clarify appropriate screening in the future, such as the INHERIT EGFR study: Investigating the hereditary risk from T790M (http://clinicaltrials.gov/ct2/show/NCT01754025).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Although data regarding EGFR T790M germline variant are limited, knowing if this variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving, and more clinically relevant data regarding EGFR are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to consider implementing proposed screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: June 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
EGFR NM_005228.3