Application of Multilayer Evidence for Annotation of C-Terminal BRCA2 Variants

Butz, Henriett; Papp, J.; Bozsik, Anikó; Krokker, Lilla; Pócza, Tímea; Oláh, Edit; Patócs, Attila

doi:10.3390/cancers13040881

Cited by 3 publications

(3 citation statements)

References 63 publications

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“…Interestingly, similar to CHEK2 , the lower penetrance BRCA2 variant p.Lys3326Ter does not appear to require biallelic activation. A recent study of 26 BRCA2 p.Lys3326Ter-associated breast tumors found no instance of LOH ( 43 ).…”

Section: Discussionmentioning

confidence: 97%

Somatic inactivation of breast cancer predisposition genes in tumors associated with pathogenic germline variants

Lim

Mahale

et al. 2022

JNCI: Journal of the National Cancer Institute

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Background Breast cancers (BC) that arise in individuals heterozygous for a germline pathogenic variant in a susceptibility gene, such as BRCA1/2, PALB2 and RAD51C, have been shown to exhibit bi-allelic loss in the respective genes, and be associated with triple-negative (TN) BC and distinctive somatic mutational signatures. Tumour sequencing thus presents an orthogonal approach to assess the role of candidate genes in BC development. Methods Exome sequencing was performed on paired normal-breast tumour DNA from 124 carriers of germline loss-of-function (LoF) or missense (MS) mutations carriers in 15 known and candidate BC predisposition genes identified in the BEACCON case-control study. Bi-allelic inactivation and association with tumour genome features including mutational signatures and homologous recombination deficiency (HRD) score were investigated. Results BARD1-carrying TN BC (4/5) displayed bi-allelic loss and associated high HRD scores and mutational signature 3, as did a RAD51D-carrying TN BC and ovarian cancer. Bi-allelic loss was less frequent in BRIP1 BCs (4/13) and had low HRD scores. In contrast to other established BC genes, BCs from carriers of CHEK2 LoF (6/17) or MS (2/20) carriers had low rates of bi-allelic loss. Exploratory analysis of BC from carriers of LoF mutations in candidate genes such as BLM, FANCM, PARP2 and RAD50 found little evidence of bi-allelic inactivation. Conclusions BARD1 and RAD51D behave as classic BRCA-like genes with bi-allelic inactivation but this was not observed for any of the candidate genes. However, as demonstrated for CHEK2, the absence of bi-allelic inactivation does not provide definitive evidence against the gene’s involvement in BC predisposition.

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Section: Discussionmentioning

confidence: 97%

Somatic inactivation of breast cancer predisposition genes in tumors associated with pathogenic germline variants

Lim

Mahale

et al. 2022

JNCI: Journal of the National Cancer Institute

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“…Of note, two of these missense variants, BRCA1 c.736T > G; p.Leu246Val and BRCA2 c.8850G > T; p.Lys2950Asn, did not affect the function of the HR pathway [ 101 , 102 ] ( Table S2 ). Although BRCA2 c.9976A > T; p.Lys3326Ter introduces a stop codon predicted to truncate the BRCA2 protein, its clinical significance remains controversial (reviewed in [ 103 , 104 ]), and this is due to: (1) the fact that its carrier frequency at 0.6% in the general population, though rare, is higher than that of other PVs in BRCA2 (0–0.001%) ( Table S2 ); and (2) its location in the C-terminus where it has been proposed to exert the least effect on the function of the protein [ 105 ]. Independent studies of sporadic and familial cancers have shown an increased risk for BC and OC in carriers of this BRCA2 variant [ 105 , 106 ].…”

Section: Genetic Analyses Of Fc Cancer Cases Facilitate the Interpretation Of Variants In Brca1 And Brca2mentioning

confidence: 99%

The Genetic Analyses of French Canadians of Quebec Facilitate the Characterization of New Cancer Predisposing Genes Implicated in Hereditary Breast and/or Ovarian Cancer Syndrome Families

Fierheller

Alenezi

Tonin

2021

Cancers

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The French Canadian population of the province of Quebec has been recognized for its contribution to research in medical genetics, especially in defining the role of heritable pathogenic variants in cancer predisposing genes. Multiple carriers of a limited number of pathogenic variants in BRCA1 and BRCA2, the major risk genes for hereditary breast and/or ovarian cancer syndrome families, have been identified in French Canadians, which is in stark contrast to the array of over 2000 different pathogenic variants reported in each of these genes in other populations. As not all such cancer syndrome families are explained by BRCA1 and BRCA2, newly proposed gene candidates identified in other populations have been investigated for their role in conferring risk in French Canadian cancer families. For example, multiple carriers of distinct variants were identified in PALB2 and RAD51D. The unique genetic architecture of French Canadians has been attributed to shared ancestry due to common ancestors of early settlers of this population with origins mainly from France. In this review, we discuss the merits of genetically characterizing cancer predisposing genes in French Canadians of Quebec. We focused on genes that have been implicated in hereditary breast and/or ovarian cancer syndrome families as they have been the most thoroughly characterized cancer syndromes in this population. We describe how genetic analyses of French Canadians have facilitated: (i) the classification of variants in BRCA1 and BRCA2; (ii) the identification and classification of variants in newly proposed breast and/or ovarian cancer predisposing genes; and (iii) the identification of a new breast cancer predisposing gene candidate, RECQL. The genetic architecture of French Canadians provides a unique opportunity to evaluate new candidate cancer predisposing genes regardless of the population in which they were identified.

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“…Locus specific loss-of-heterogeneity (LOH) was tested as previously described [8]. Briefly, DNA from tumor tissues was used for PCR amplification by a Qiagen Multiplex PCR Kit (Qiagen).…”

Section: Sanger Validation and Loh (Loss Of Heterozygosity) Analysismentioning

confidence: 99%

Surprising genetic and pathological findings in a patient with giant bilateral periadrenal tumours: PEComas and mutations of PTCH1 in Gorlin-Goltz syndrome

Igaz

Tóth²,

Dezső

et al. 2021

J Med Genet

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Gorlin-Goltz syndrome (GGS) or nevoid basal cell carcinoma syndrome is a rare tumour-overgrowth syndrome associated with multiple developmental anomalies and a wide variety of tumours. Here, we describe a case of a man aged 23 years with GGS with bilateral giant tumours adjacent to both adrenals that raised the suspicion of malignancy on imaging. Histological analysis of both surgically resected tumours revealed perivascular epitheloid cell tumours (PEComas) that were independent of the adrenals. Exome sequencing of the patient’s blood sample revealed a novel germline heterozygous frameshift mutation in the PTCH1 gene. As a second hit, a somatic five nucleotide long deletion in the PTCH1 gene was demonstrated in the tumour DNA of both PEComas. To the best of our knowledge, this is the first report on PEComa in GGS, and this finding also raises the potential relevance of PTCH1 mutations and altered sonic hedgehog signalling in PEComa pathogenesis. The presence of the same somatic mutation in the bilateral tumours might indicate the possibility of a postzygotic somatic mutation that along with the germline mutation of the same gene could represent an intriguing genetic phenomenon (type 2 segmental mosaicism).

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Application of Multilayer Evidence for Annotation of C-Terminal BRCA2 Variants

Cited by 3 publications

References 63 publications

Somatic inactivation of breast cancer predisposition genes in tumors associated with pathogenic germline variants

Somatic inactivation of breast cancer predisposition genes in tumors associated with pathogenic germline variants

The Genetic Analyses of French Canadians of Quebec Facilitate the Characterization of New Cancer Predisposing Genes Implicated in Hereditary Breast and/or Ovarian Cancer Syndrome Families

Surprising genetic and pathological findings in a patient with giant bilateral periadrenal tumours: PEComas and mutations of PTCH1 in Gorlin-Goltz syndrome

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