Skip to 0 minutes and 0 secondsOccasionally we get variants which can’t be classified one way or another because there isn’t enough evidence to say that they don’t cause disease or enough evidence to say that they do cause the disease and these are the variants of uncertain significance. The difficulty when you receive a variant of uncertain significance is how you use that information both for the patient in front of you, but also how you use that information for their family members. We had a case with a patient who had been referred to the hospital for predictive testing because her sister had undergone testing in another country and been found to have a variant of uncertain significance in BRCA2.

Skip to 0 minutes and 37 secondsThey had a number of relatives who’d died at young ages, of breast and ovarian cancer, so they were worried about their own risk of developing these cancers. The patient in another country was told that this was probably the cause of the cancer in the family and she went on to have both of her breasts removed. She was also planning to have her ovaries removed at a later date as a risk reducing procedure. And then she told her sister to be tested for this mutation to see if she needed the same treatment.

Skip to 1 minute and 4 secondsSo this sister turned up to have this testing undertaken, she made it very clear at her appointment that she wanted to have the same surgery that her sister had had if she was found to carry this variant. But when we received a copy of the mutation report it was clear to us that this was not a variant that was definitively associated with the cancer. Nine months later this particular variant was reclassified internationally as non-disease causing. So the woman overseas has had unnecessary major surgery and we still don’t know whether or not either of the sisters is at risk of developing cancer in future because its not clear to us what the cause of the cancer in the family is.

Skip to 1 minute and 47 secondsBoth of these sisters had daughters who were both also poised to have testing and potentially have the same, quite dramatic, surgery which would have again been unnecessary. I think the most important things to take away from the case are knowing your limitations when you request testing and you have to know the limitations of how you can interpret them and what should and shouldn’t be done for these patients.

Skip to 2 minutes and 8 secondsAs we’re moving forward into the genomic medicine era and an era of personalised medicine we do have to be careful as clinicians that we’re not making an error both for the patient in front of us and the implications for their treatment, but also amplifying any potential errors across their family members as well.

The impact of incorrect reporting

In this video, Dr Angela George, Consultant in Oncogenetics, outlines the importance of exercising caution when reporting variants, discussing the challenge posed by variants of uncertain significance.

Dr George describes a case where a woman came to her clinic for predictive testing on the advice of her sister, who had had testing in another country and was found to have a variant of uncertain significance in BRCA2. The woman’s sister was told that this variant was probably responsible for the breast and ovarian cancers that were prevalent in their family, and had a double mastectomy based on this advice. (She was also planning to return to hospital to have both of her ovaries removed as a risk-reducing measure).

As Dr George explains, however, by UK classification, this variant was not deemed to have sufficient evidence linking it to breast and ovarian cancer, so no action would have been taken in the NHS. Then, nine months later, the variant was re-classified as non-pathogenic (non-disease-causing), meaning her patient’s sister had had drastic and unnecessary surgery.

This example drives home the importance of careful and accurate reporting.

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Whole Genome Sequencing: Decoding the Language of Life and Health

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