ClinVar

Description

Variant summary: BRCA2 c.4141_4143delAAA (p.Lys1381del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 245496 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4141_4143delAAA was reported in a hereditary breast cancer patient sample, however, the variant was designated as a false postivie for a different true indel (c.4146_4148delAGA; Bosdet_2013). The variant was also previously identified in a BRCA1/BRCA2 sequencing dataset, however, no genotype-phenotype, co-occurrence, or co-segregation data was provided; in these studies, in silico analyses predicted the variant to be neutral and likely benign (Parsons_2019, Cline_2019, Padilla_2019). These reports do not provide conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.