ClinVar

Description

Variant summary: BRCA2 c.426-12_426-8delGTTTT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Two computational tools predict the variant weakens a 3' acceptor site. In addition, a recent computational study predicted a high probability of splicing impact (Leman_2018). Several publications reported experimental evidence that this variant affects mRNA splicing, by increasing exon 5 skipping (predicted to result in a frameshift), and consequently decreasing the expression of the full-length transcript (e.g., Zhang_2009, Sanz_2010, Whiley_2011, Whiley_2014, Lattimore_2018, Fraile-Bethencourt_2019). However, a more recent study found that this aberrant splicing is inefficient and the percent splicing index (PSI) was determined to be ~20% in positive controls (vs. ~10% in healthy controls) (Landrith_2020); the amount of normal transcript needed for normal BRCA2 function is unknown (Nix_2020). The variant was absent in 249586 control chromosomes (gnomAD). c.426-12_426-8delGTTTT has been reported in the literature in individuals affected with breast cancer, as well as unaffected individuals (e.g., Zhang_2009, Whiley_2011, Susswein_2015). These reports do not allow any conclusion about variant significance. Multiple co-occurrences with other pathogenic variants have been reported (BRCA2 c.9257-1G>C [NHGRI BIC database, Nix_2020]; BRCA2 c.7248del, p.H2417TfsX50 [LOVD database]; BRCA1 c.5152+1G>T [Loughrey_2008]; BRCA2 c.7719dupA, p.W2574MfsX10 [Nix_2020]), providing supporting evidence for a benign role. Particularly, Nix et al (2020) report carriers of the variant did not have a personal or family history consistent with pathogenicity and they specify that the variant was found to co-occur in trans with two different pathogenic variants in BRCA2 in individuals with no known features of Fanconi anemia. The following publications have been ascertained in the context of this evaluation (PMID: 26992833, 27060066, 30675319, 30883759, 21702907, 31642931, 29774201, 29750258, 18446624, 20215541, 26681312, 24212087, 21394826, 19070627, 32133419, 35050751). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014; 7 submitters classified the variant as VUS, and 1 submitter classified it as likely benign. Based on the evidence outlined above, the variant was re-classified as VUS-possibly benign.