BRCA2 NM_000059.4:c.1238del, Leu413HisfsTer17

Variant summary: BRCA2 c.1238delT (p.Leu413HisfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 249956 control chromosomes (gnomAD). c.1238delT has been reported in the literature and in at least one clinical database in multiple individuals and families affected with breast and/or ovarian cancer (e.g. Giannini_2006, Caux-Moncoutier_2011, Manie_2016, Coppa_2014, Tedaldi_2020, BIC database). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The c.1238delT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1238, causing a translational frameshift with a predicted alternate stop codon (p.L413Hfs*17). This alteration has been identified in numerous Italian families with bilateral breast cancer, male breast cancer, and ovarian cancer histories (Capalbo C et al. Ann. Oncol., 2006 Jun;17 Suppl 7:vii34-40; Giannini G et al. Breast Cancer Res Treat, 2006 Nov;100:83-91; Minucci A et al. Expert Rev Mol Diagn, 2015 Aug;15:1383-403; Fanale D et al. Cancers (Basel), 2020 Aug;12(9); Incorvaia L et al. Cancers (Basel), 2020 May;12(5)). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

This sequence change creates a premature translational stop signal (p.Leu413Hisfs*17) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 16760289, 21120943, 26306726). This variant is also known as 1466delT. ClinVar contains an entry for this variant (Variation ID: 37731). For these reasons, this variant has been classified as Pathogenic.

PM5_strong, PVS1

The BRCA2 c.1238delT (p.Leu413HisfsTer17) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Leu413HisfsTer17 has been reported in eight studies in which it has been identified in a heterozygous state in at least 11 individuals with hereditary cancer, either breast cancer, breast cancer and ovarian cancer or ovarian cancer alone (Capalbo et al. 2006; Giannini et al. 2006; Caux-Moncoutier et al. 2011; Concolino et al.2014; Coppa et al. 2014; Minucci 2015; Manie et al. 2016; Palmero et al. 2018). The variant is reported at a frequency of 0.000009 in the European (non-Finnish) population from the Genome Aggregation Database but this is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. Although the c.3201+1G>C variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of condition penetrance and prevalence estimates. Based on the evidence and the potential impact of frameshift variants, the BRCA2 p.Leu413HisfsTer17 variant is classified as pathogenic for hereditary breast and ovarian cancer. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.