Concurrent pathogenic variations in patients with hereditary cancer syndromes

Ağaoğlu, Nihat Buğra; Doganay, Levent

doi:10.1016/j.ejmg.2021.104366

Cited by 8 publications

(3 citation statements)

References 35 publications

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“…Therefore, NGS has implemented the potential for the detection of pathogenic variants in HBOC genes other than BRCA1 and BRCA2 and for the identification of subjects with pathogenic variants in more than one cancer predisposition gene. In fact, although not frequently, HBOC patients have been described with double heterozygous pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, MSH6, MUTYH, NBN/NBS1 and RAD50 following gene panel testing (7)(8)(9)(10)(11)(12)(13) with a frequency of approximately 0.3% (10,13). Not surprisingly, double heterozygous carriers are more frequently detected in populations enriched with founder variants (14).…”

Section: Introductionmentioning

confidence: 99%

A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report

et al. 2023

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The widespread adoption of gene panel testing for cancer predisposition is leading to the identification of an increasing number of individuals with clinically relevant allelic variants in two or more genes. The potential combined effect of these variants on cancer risks is mostly unknown, posing a serious problem for genetic counseling in these individuals and their relatives, in whom the variants may segregate singly or in combination. We report a female patient who developed triple-negative high grade carcinoma in the right breast at the age of 36 years. The patient underwent bilateral mastectomy followed by combined immunotherapy and chemotherapy (IMpassion030 clinical trial). Two years later she developed a skin recurrence on the right anterior chest wall. Despite intensive treatment, the patient died at 40-year-old due to disease progression. Gene panel testing of patient’s DNA revealed the presence of a protein truncating variant in ATM [c.1672G>T; p.(Gly558Ter)] and of a not previously reported variant in the BRCA1 exon 22 donor splice site [c.5406+6T>C], whose clinical significance was unknown. The analysis of patient’s RNA revealed the up-regulation of two alternative BRCA1 mRNA isoforms derived from skipping of exon 22 and of exons 22-23. The corresponding predicted protein products, p.(Asp1778GlyfsTer27) and p.(Asp1778_His1822del) are both expected to affect the BRCA1 C Terminus (BRCT) domain. The two variants were observed to co-occur also in the proband’s brother who, in addition, was heterozygous for a common variant (c.4837A>G) mapped to BRCA1 exon 16. This allowed to ascertain, by transcript-specific amplification, the lack of functional mRNA isoforms expressed by the c.5406+6T>C allele and provided evidence to classify the BRCA1 variant as pathogenic, according to the guidelines of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium. To our knowledge, excluding two cases detected following the screening of population specific recurrent variants, only one ATM/BRCA1 double heterozygote has been reported in the literature, being the case here described the one with the youngest age at cancer onset. The systematic collection of cases with pathogenic variants in more than one cancer predisposition gene is needed to verify if they deserve ad hoc counseling and clinical management.

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Section: Introductionmentioning

confidence: 99%

A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report

et al. 2023

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“…In early-onset breast cancer, concurrent germline variants of BRCA1 , BRCA2 , PMS2 , and PALB2 were reported [ 36 ]. Analysis of hereditary cancer cases (732 BC patients, 189 CRC patients, and 490 cancer-free elderly controls) revealed that 1% presented concurrent germline pathogenic variants in BRCA1 , BRCA2 , MUTYH , ATM , CHECK2 , NBN , and RAD50 [ 37 ]. The germline genomic profile of BC/CRC patients fulfilling the criteria of HBOC and HBCC is poorly explored in the literature.…”

Section: Discussionmentioning

confidence: 99%

Co-Occurrence of Germline Genomic Variants and Copy Number Variations in Hereditary Breast and Colorectal Cancer Patients

Cortes

Basso²,

Villacis

et al. 2023

Genes

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Hereditary Breast and Ovarian Cancer (HBOC) syndrome is an autosomal dominant disease associated with a high risk of developing breast, ovarian, and other malignancies. Lynch syndrome is caused by mutations in mismatch repair genes predisposing to colorectal and endometrial cancers, among others. A rare phenotype overlapping hereditary colorectal and breast cancer syndromes is poorly characterized. Three breast and colorectal cancer unrelated patients fulfilling clinical criteria for HBOC were tested by whole exome sequencing. A family history of colorectal cancer was reported in two patients (cases 2 and 3). Several variants and copy number variations were identified, which potentially contribute to the cancer risk or prognosis. All patients presented copy number imbalances encompassing PMS2 (two deletions and one duplication), a known gene involved in the DNA mismatch repair pathway. Two patients showed gains covering the POLE2 (cases 1 and 3), which is associated with DNA replication. Germline potentially damaging variants were found in PTCH1 (patient 3), MAT1A, and WRN (patient 2). Overall, concurrent genomic alterations were described that may increase the risk of cancer appearance in HBOC patients with breast and colorectal cancers.

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“…The presence of two or more CSGs is labeled Multi-locus Inherited Neoplasia Allele Syndrome (MINAS) and was described by Whitworth and colleagues in 2016 2 . MINAS is rare, ranging from 0.1 to 2%, but increasing in detection as testing capabilities expand 6,7,8 . In a systematic review of 385 MINAS cases, over 70% contained at least one pathogenic variant inBRCA1 or BRCA2 7 , a historically widely tested gene.…”

Section: Nf1mentioning

confidence: 99%

A child possessing a concurrent germline NF1 variant and a mosaic TP53 variant: A rare case discussion

Ball-Burack,

Waligorski

et al. 2024

Preprint

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Concurrent pathogenic variations in patients with hereditary cancer syndromes

Cited by 8 publications

References 35 publications

A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report

A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report

Co-Occurrence of Germline Genomic Variants and Copy Number Variations in Hereditary Breast and Colorectal Cancer Patients

A child possessing a concurrent germline NF1 variant and a mosaic TP53 variant: A rare case discussion

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