ClinVar

Description

The BRCA2 p.Lys944X variant was identified in 8 of 25752 proband chromosomes (frequency: 0.0003) from individuals or families with breast and ovarian cancer (Blay 2013, Borg 2010, Capalbo 2006, Hakansson 1997, Heramb 2018, Susswein 2015). The variant was also identified in the following databases: dbSNP (ID: rs80358533) as "With Pathogenic allele", ClinVar (12x pathogenic), Clinvitae (5x pathogenic), GeneInsight-COGR (2x pathogenic), Cosmic (1x, confirmed somatic, in carcinoma of the biliary tract), LOVD 3.0 (11x), UMD-LSDB (8x causal), BIC Database (6x pathogenic), and ARUP Laboratories (pathogenic). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 3 of 276604 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 23994 chromosomes (freq: 0.00004), European in 1 of 126388 chromosomes (freq: 0.000008), and South Asian in 1 of 30678 chromosomes (freq: 0.00003). The variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The c.2830A>T variant leads to a premature stop codon at position 944 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.