Ataxia–Telangiectasia Gene (ATM) Mutation Heterozygosity in Breast Cancer: A Narrative Review

Jerzak, Katarzyna J.; Mancuso, T.; Eisen, Andrea

doi:10.3747/co.25.3707

Cited by 78 publications

(57 citation statements)

References 71 publications

(97 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Exceptions to this definition were made for couples who were carrier matches but were not classified as being at risk to have an affected fetus, specifically those who were both silent alpha thalassemia carriers and those with the R229Q variant in NPHS2 that unless when co‐inherited with specific variants is not believed to cause steroid resistant nephrotic syndrome . Additionally, couples were not considered at‐risk if there was a chance for their offspring to inherit a heterozygous pathogenic variant that could present with adult‐onset symptoms in carriers (such as for GBA, and ATM, among others).…”

Section: Methodsmentioning

confidence: 99%

It takes two: uptake of carrier screening among male reproductive partners

et al. 2019

View full text Add to dashboard Cite

Objective To describe uptake of carrier screening by male reproductive partners of prenatal and preconception patients. Methods A retrospective database review of all prenatal and preconception patients seen for genetic counseling in Maternal Fetal Medicine clinics was performed. Descriptive statistics and chi‐square analysis were used on the data set. Results Within the study period, 6087 patients were seen for genetic counseling, of whom 661 were identified as a carrier of an autosomal recessive disorder by their referring provider or genetic counselor. Despite guidelines recommending partner testing for risk clarification when a woman is known to be a carrier of an autosomal recessive condition, only 41.5% male partners elected carrier screening to clarify the couple's reproductive risk, with a majority of males (75%) having screening consecutively. Of all assessed variables, the only significant predictors of male carrier screening uptake were female parity and earlier gestational age (p < .0001, and p = .001, respectively). Conclusion With less than half of male partners pursuing carrier screening when indicated, its utility becomes severely diminished. More research is needed to explore reasons why males elect or decline carrier screening.

show abstract

Section: Methodsmentioning

confidence: 99%

It takes two: uptake of carrier screening among male reproductive partners

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Differently from A-T patients, who carry almost exclusively nonsense truncating mutations, cancer patients bear more heterogeneous types of variants. These include out-of-frame mutations with premature stop-codon formation, splicing-affecting variants, synonymous, missense and intronic mutations, with much less evident functional impact, and are enriched in VUS [71,75]. In the last decade, it has been shown that cell models with ATM mutations that cause low or no protein expression are more sensitive to PARPi, supporting clinical implications similar to those of BRCA1/2 mutant carriers.…”

Section: Atm Variants and A New Possible Functional Assay: The P53 MImentioning

confidence: 98%

“…Up to 2% of the whole human population is heterozygous for a pathogenic ATM variant and it has been demonstrated that healthy carriers, such as the parents of A-T patients, are more susceptible to tumor formation, with a 5-to 9-fold increased risk of breast cancer in women [69,70]. Heterozygotes are also sensitive to damage from radio-and chemo-therapy [69][70][71][72][73]. Moreover, it has been demonstrated that rare missense variants of moderate-risk genes, such as ATM, confer an increased risk for early-onset breast cancer [74].…”

Section: Atm Variants and A New Possible Functional Assay: The P53 MImentioning

confidence: 99%

Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers

Federici¹,

Soddu²

2020

J Exp Clin Cancer Res

135

109

View full text Add to dashboard Cite

The promising expectations about personalized medicine have opened the path to routine large-scale sequencing and increased the importance of genetic counseling for hereditary cancers, among which hereditary breast and ovary cancers (HBOC) have a major impact. High-throughput sequencing, or Next-Generation Sequencing (NGS), has improved cancer patient management, ameliorating diagnosis and treatment decisions. In addition to its undeniable clinical utility, NGS is also unveiling a large number of variants that we are still not able to clearly define and classify, the variants of uncertain significance (VUS), which account for about 40% of total variants. At present, VUS use in the clinical context is challenging. Medical reports may omit this kind of data and, even when included, they limit the clinical utility of genetic information. This has prompted the scientific community to seek easily applicable tests to accurately classify VUS and increase the amount of usable information from NGS data. In this review, we will focus on NGS and classification systems for VUS investigation, with particular attention on HBOCrelated genes and in vitro functional tests developed for ameliorating and accelerating variant classification in cancer.

show abstract

“…Homozygous mutations in ATM gene cause ataxiatelangiectasia, cerebellar ataxia associated immunodeficiency syndrome 10 , while heterozygous mutations predispose to pancreatic and prostate cancer, particularly in women with breast cancer. Life-long breast cancer risk is up to 25% in women with pathogenic heterozygous ATM mutations 11 . Both pathogenic variants of ATM are a nonsense alteration.…”

Section: Discussionmentioning

confidence: 99%

Multigene panel testing for hereditary breast cancer: An analysis of 70 BRCA-negative Turkish patients

Erdem

Bahsi

2019

Cumhuriyet Medical Journal

View full text Add to dashboard Cite

Although the molecular etiology of breast cancer is not clearly known, hereditary genetic causes are responsible for approximately 10%. In addition to BRCA1 and BRCA2 genes, there are many genes that cause breast cancer. In this study, we performed a hereditary cancer genetic panel test among hereditary breast cancer patients who are negative for BRCA1 and BRCA2 genes. Accordingly, the frequency of mutations, causing hereditary cancer among Turkish breast cancer patients, was investigated. Method: All the 70 patients were unrelated and provided BRCA testing criteria according to the National Comprehensive Cancer Network guidelines, but they were reported as unfavorable. Qiagen large hereditary cancer panel and Hereditary Cancer Solution v1.1 panel were used for sequencing. The sequencing process was performed on the Illumina MiSeq system. The data analyses were performed on QIAGEN Clinical Insight (QCI™) Analyze software and Sophia DDM software. Results: Of 70 patients, 6 (8.5%) were found to carry a pathogenic, and 1 (1.4%) were found to give a likely pathogenic mutation. Pathogenic variants were detected in ATM, NBN, PTEN, RAD51C genes; the likely pathogenic variant was discovered in the MUTYH gene. Only, PTEN:c.407G>A mutation was found in two patients; the other mutations were detected once in each patient. A nonsense alteration, RAD51C:c.907G>T, was described as a novel variant. The variant of uncertain significance variants was detected in 10 patients (14.2%). Conclusions: It is essential to perform the hereditary cancer panel from index cases in families with high cancer incidence, whose BRCA1/2 negative and molecular background has not been elucidated, for preventive health policies. In addition, the identification of common familial cancer genes will guide personalized therapy planning.

show abstract

Ataxia–Telangiectasia Gene (ATM) Mutation Heterozygosity in Breast Cancer: A Narrative Review

Abstract: Background Despite the fact that heterozygosity for a pathogenic ATM variant is present in 1%-2% of the adult

Cited by 78 publications

References 71 publications

It takes two: uptake of carrier screening among male reproductive partners

It takes two: uptake of carrier screening among male reproductive partners

Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers

Multigene panel testing for hereditary breast cancer: An analysis of 70 BRCA-negative Turkish patients

Contact Info

Product

Resources

About