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Oncology

Results: Patient with breast cancer and a constitutional (germline) pathogenic ATM variant

The identification of a constitutional (germline) pathogenic variant in the ATM gene in a patient with breast cancer may have implications for the clinical management of the current cancer, as well as for the patient’s future cancer risk. It should also trigger cascade testing in the wider family.

Example clinical scenario

A 37-year-old woman is diagnosed with a grade-two oestrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative T2N0M0 left-sided breast cancer. In view of her age, she is referred for constitutional (germline) testing of the breast cancer susceptibility genes. The National Genomic Test Directory R208 panel is performed, testing for variants in BRCA1, BRCA2 and PALB2 and for truncating or exceptional missense variants in ATM, CHEK2, RAD51C and RAD51D. A pathogenic truncating variant in the ATM gene is reported.

Impact of the genomic result

PIK3CA variants in ER-positive, HER2-negative breast cancer

  • ATM is a tumour suppressor gene and encodes a multi-functional protein. Activation of ATM by double-stranded DNA damage results in initiation of the homologous recombination repair (HRR) pathway.
  • Pathogenic ATM variants are found in around 1% of the population. Most ATM variants are single nucleotide variants but larger deletions have been reported.
  • Constitutional (germline) pathogenic variants in ATM are associated with moderately increased risks of breast, ovarian, pancreatic and prostate cancers. The magnitude of the increase in cancer risk varies according to the individual genetic variant, with truncating variants associated with higher risk than most missense variants. Those missense variants associated with more modest risk are not currently analysed or reported by NHS labs. Further detail is available through the UK Cancer Genetics Group.
  • The risk of second primary breast cancers in individuals with likely pathogenic or pathogenic variants in ATM is uncertain, but there is some evidence to suggest it is increased.

What do you need to do?

Management of the current cancer

  • There is a lack of survival and surgical outcome data on ATM-associated breast cancers. Currently, there is insufficient evidence to recommend risk-reducing mastectomy purely on the basis of an ATM variant, and the decision should be guided by family history in addition to the patient genotype.
  • Radiotherapy is not contraindicated in heterozygous carriers of ATM variants based on current evidence, but is contraindicated in carriers of biallelic variants, who are affected by ataxia telangiectasia – an autosomal recessive condition associated with progressive neurological degeneration, immunodeficiency, increased cancer risk and radiosensitivity.
  • PARP inhibitors are currently not licensed for use in breast cancer patients with constitutional (germline) ATM variants. The effectiveness of PARP inhibitors in this patient group is under investigation in clinical trials.

Further somatic (tumour) testing

  • No additional somatic testing is routinely indicated in this clinical scenario.

Management of the patient’s risk of further primary cancers

Individuals with inherited genomic variants associated with high risk of cancer can manage their cancer risk through a combination of surveillance, risk-reducing surgery and other techniques. The exact advice provided to those with gene variants will be individualised, depending on their result and associated cancer risk, as well as on the treatment and overall prognosis of their current cancer.

Management of the family’s risk

  • Cancer predisposition associated with heterozygous ATM constitutional (germline) variants is inherited in an autosomal dominant pattern. Biallelic variants in ATM are associated with ataxia telangiectasia, which may be of relevance in family planning for patients in consanguineous relationships.
  • First-degree relatives (children or siblings) of an individual with an inherited pathogenic variant in ATM are at a 50% risk (one in two) of inheriting the familial variant. Because most pathogenic ATM variants are inherited from a parent, the parents of an affected individual should also be offered genomic testing.
  • Patients with breast cancer found to have a constitutional (germline) ATM variant should be referred to clinical genetics to discuss implications of the result for them and for their family members, and to facilitate cascade testing of relatives.

Family planning implications

The Human Fertilisation and Embryology Authority have approved the use of preimplantation genetic testing (formerly called preimplantation genetic diagnosis) for couples in whom one or both intended parents have a (likely) pathogenic variant associated with a significant risk of cancer or other pathology. At present, HFEA approval for PGT-M exists where a couple is at risk of having a child with ataxia telangiectasia, or where at least one intended parent is a carrier of the high-risk variant ATM: c.7271T>G, but approval could be sought for testing for other variants, if appropriate, by the clinical genetics service.

Other options may include prenatal testing (invasive, or non-invasive if the potential father has the variant) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children in adulthood.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 30/08/2024
  • Next review due: 30/08/2025
  • Authors: Dr Ellen Copson
  • Reviewers: Dr Terri McVeigh

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