ClinVar

Description

Variant summary: BRCA2 c.5554G>A (p.Val1852Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 295242 control chromosomes (gnomAD and Momozawa_2018). This frequency is lower than the estimated maximum expected for a pathogenic (MPAF) variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (0.00075). In addition, the variant was also reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.000388 (in the jMorp database), although this frequency is also somewhat lower than the MPAF, allowing no clear conclusions about variant significance. c.5554G>A has been reported in the literature in individuals affected with breast- and/or ovarian cancer (e.g. Momozawa_2018, Dorling_2021, Lee_2018, Kim_2020, Kim_2021), and other cancers (Haiman_2013, Dame_2018), as well as in healthy controls (Momozawa_2018, Dorling_2021). Co-occurrences with other pathogenic variants have been reported (BRCA2 c.9076C>T / p.Gln3026X in LOVD, and BRCA1 c.5467+1G>A in two internal LCA samples), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A large scale study utilizing multifactorial probability model for quantitative analysis of BRCA1 and BRCA2 variants predicted this variant to be likely benign (Parsons_2019). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and multiple laboratories reported the variant with conflicting assessments (VUS, n = 5; likely benign, n = 4). Based on the evidence outlined above, the variant was classified as likely benign.