Every individual's genetic makeup is unique, containing the blueprint for their health, including susceptibility to diseases and potential response to treatments. But understanding your genes is like deciphering a complex code. DNA varies slightly from person to person, and interpreting the medical significance of those differences, or variants, is one of the most important steps in genetic testing. That's where accurate genetic variant classification comes into play. Variant interpretation is often complicated. There are many pieces of clinical, statistical and functional evidence that need to fit together, and this can require the collaboration of many individuals and institutions.
We talked with genetic counselors Briana Marmelstein and Avi Anantharajah about how they experienced this firsthand during a challenging case involving a suspicious CDH1 variant. We explored how a multidisciplinary journey and a passion for helping patients drove everyone working on this case. Check out highlights of that interview:
Pathogenic (harmful) variants in the CDH1 gene increase lifetime risks for diffuse gastric cancer and lobular breast cancer.1 People with pathogenic variants in CDH1 have markedly different medical management recommendations compared to the general population, including the option for preventive removal of the stomach due to the high lethality of diffuse gastric cancer.1 Therefore, accurate interpretation of CDH1 variants is critical. However, when a variant is first identified in an individual, it can be difficult to tell if it’s pathogenic or benign (harmless). It is not uncommon to have limited, incomplete or conflicting evidence available when working to classify a variant. A genetic variant is classified as a variant of uncertain significance (VUS) when there is not enough evidence to confirm the variant is either pathogenic or benign.
In this case example, Briana and Avi’s patient was a 45-year-old woman with lobular breast cancer and a family history of gastric cancer on her father’s side. However, the type of gastric cancer was unknown. Several women on her mother’s side had breast cancer. Based on her personal and family history, she met criteria for genetic testing, and DNA-only sequencing at the initial testing lab identified an intronic VUS. An intron is a gene region that does not code for a protein. Variants in introns can be harder to interpret. Hoping to gain more information, the patient’s genetic counselors ordered paired DNA and RNA testing at Ambry, confirming the finding of the VUS (c.833-9C>G). Two different RNA testing methods were used to better understand the effect of this variant, which can increase confidence in the result and its interpretation. For more information, read the publication on this case in Familial Cancer. However, RNA must be interpreted in the context of clinical evidence, and RNA evidence alone was insufficient to classify this variant as likely pathogenic.
At the same time Ambry was performing RNA testing, Briana and Avi’s patient was receiving treatment for her breast cancer and making decisions about future cancer risk reduction. Based on her father’s history of gastric cancer, she underwent an upper endoscopy and biopsy of the stomach. Surprisingly, a small focus of diffuse gastric cancer cells was found in one of the biopsy samples. The patient subsequently pursued a total gastrectomy (removal of stomach), and several small diffuse gastric cancer tumors were confirmed. This means her surgery was potentially lifesaving.
Knowing the importance of sharing clinical data with testing laboratories, the patient’s genetic counselors provided the updated diagnosis of diffuse gastric cancer with Ambry. Furthermore, Ambry reached out to another lab and discovered that the c.833-9C>G variant had been identified in an additional patient with diffuse gastric cancer. With these clinical updates, together with the existing RNA data, there was now enough evidence to reclassify the variant from VUS to likely pathogenic. Thanks to the teamwork of the genetic counselors and multiple labs, this result could then be used to inform the medical plans of the original patient, her family members and any other individual with this variant in the future. Avi describes the deciphering of this result as a “remarkable lift that was taken on by the clinicians as well as the laboratory.” Briana agreed and shared, “I really think if you ask anyone involved on the case, the key word is ‘collaboration,’ the collaboration of every single person involved, from the patient to the lab to the clinicians.”
This story demonstrates the importance of data transparency, stewardship and teamwork to best serve clinicians, patients and the field of Genetics and Genomics. Avi reflected on this: “I think it should be a reminder for us that there's information out there that could potentially lead to some clarity when it comes to variants and interpretation. How much information are we leaving out there by not sharing it with each other, by not sharing it with laboratories or by laboratories not sharing with each other?”
In an ideal state, geneticists, lab technicians, bioinformaticians, researchers, providers and patients all work together to incorporate complex data and human stories. Sometimes it takes a village.
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1. Kaurah P, Huntsman DG. Hereditary Diffuse Gastric Cancer. 2002 Nov 4 [Updated 2018 Mar 22]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1139/
