Gene panel testing for breast cancer should not be used to confirm syndromic gene associations

In recent years, there has been an explosion in the use of multi-gene panels to test for cancer predisposition often utilising large panels across many tumour types. More recently, the results of these tests have been used as a form of case control study to assess genes for cancer associations, especially with breast cancer. Four recent articles based on multi-gene panel testing, published in high impact oncology journals, have concluded that there are no associations between pathogenic variants in three syndromic genes ( NF1, PTEN and STK11 ) and breast cancer risk. 1 , 2 , 3 , 4 Whilst these analyses have identified potential new gene associations, the negative results concerning syndromic associations should be tempered. In the first of their three articles, Ambry’s 21 panel gene test 1 was evaluated in 41,611 consecutively tested white women with breast cancer. In the second, 2 9639 patients with breast cancer were assessed, whilst the third assessed the risk of triple negative breast cancer in 8753 women. 3 Whilst two studies used control data from the ExAc database 1 , 3 the second used a combination of controls tested for non-cancer indications. 2 The larger initial study 1 identified NF1 gene variants in 0.1% compared to 0.11% in ExAc controls. No control frequency was provided for the second study 2 although a frequency in cases of around 0.15% was said to be non-significant. 2 The third study also found a frequency of 0.15% in triple negative breast cancer which was also non-significant. 3 The first two studies effectively excluded BRCA1 and BRCA2 as they confirmed that there had been a high degree of pre-testing for these genes. The first also excluded what they ‘termed’ ‘syndromic’ genes including PTEN, CDH1 and TP53 . However, it is unclear why neurofibromatosis 1, caused by pathogenic variants in the NF1 gene, was not also excluded as being syndromic, as it is far more recognisable from patient characteristics than even PTEN hamartoma syndrome. 5