<scp>ATM</scp> c.<scp>7570G</scp>&gt;C is a high‐risk allele for breast cancer

Kankuri-Tammilehto, Minna; Tervasmäki, Anna; Kraatari, Minna; Rahikkala, Elisa; Pylkäs, Katri; Kuismin, Outi

doi:10.1002/ijc.34305

Cited by 3 publications

(1 citation statement)

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“…The presence of other known susceptibility alleles was investigated in these nine CNV carriers using the SNV calls from whole-exome sequencing [ 18 ]. One case with RAD51C duplication was found to carry the ATM c.7570G>C (p.Ala2524Pro) allele, recently established to confer a high-risk for breast cancer [ 19 ], whereas the rest had no other known moderate-to-high risk predisposing alleles.…”

Section: Resultsmentioning

confidence: 99%

Exome sequencing identified rare recurrent copy number variants and hereditary breast cancer susceptibility

Kumpula,

Vorimo,

Mattila

et al. 2023

PLoS Genet

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Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10–7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31–8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62–31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.

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Section: Resultsmentioning

confidence: 99%

Exome sequencing identified rare recurrent copy number variants and hereditary breast cancer susceptibility

Kumpula,

Vorimo,

Mattila

et al. 2023

PLoS Genet

Self Cite

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ATM c.7570G>C is a high‐risk allele for breast cancer

Kankuri-Tammilehto

Tervasmäki

Kraatari

et al. 2022

Intl Journal of Cancer

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ATM is generally described as a moderate-risk breast cancer susceptibility gene. However, some of ATM variants might encounter higher risk. ATM c.7570G>C, p.Ala2524Pro, (rs769142993) is a pathogenic Finnish founder variant causative for recessively inherited ataxia-telangiectasia. At cellular level, it has been reported to have a dominant-negative effect. ATM c.7570G>C has recurrently been described in Finnish breast cancer families and unselected case cohorts collected from different parts of the country, but the rarity of the allele (MAF 0.0002772 in Finns) and lack of confirming segregation analyses have prevented any conclusive risk estimates. Here, we describe seven families from genetic counseling units with ATM c.7570G>C variant showing co-segregation with breast cancer.Further analysis of the unselected breast cancer cohort from Northern Finland (n = 1822), a geographical region previously indicated to have enrichment of the variant, demonstrated that c.7570G>C significantly associates with breast cancer, and the risk is estimated as high (odds ratio [OR] = 8.5, 95% confidence interval [CI] = 1.04-62.46, P = .018). Altogether, these results place ATM c.7570G>C variant among the high-risk alleles for breast cancer, which should be taken into consideration in genetic counseling.

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