ClinVar

Description

The BRCA2 p.Ser973= variant was identified in 4 of 3750 proband chromosomes (frequency: 0.001) from Spanish, Cypriot, Greek, Italian and American individuals or families with FCCX (familial crc type X), and breast/ovarian (sporadic and familial) cancers and was not identified in 100 chromosomes from healthy individuals (Garre 2015, Hadjisavvas 2004, Konstantopoulou 2007, Minucci 2015, Borg 2010). The variant was also identified in dbSNP (ID: rs45525041) “With other allele”, ClinVar (classified benign, reviewed by an expert panel (June 2017); submitters: benign by ENIGMA, Invitae, GeneDx and Baylor Miraca Genetics Laboratories; likely benign by Ambry Genetics, CHEO, Counsyl, Illumina; and uncertain significance by BIC), Clinvitae (6x), LOVD 3.0 (1x), UMD-LSDB (36x as 3-uv, co-occurring with BRCA1 pathogenic variants: c.5123C>A; p.Ala1708Glu, c.5266dup; p.Gln1756ProfsX74, c.2722G>T; p.Glu908X), and BIC Database (1x, clinical importance unknown, classification pending). The variant was not identified in COGR, Cosmic, ARUP Laboratories, and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 88 of 275074 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Breakdown of the observations by population include Latino in 7 of 34050 chromosomes (freq. 0.0002), European Non-Finnish in 33 of 125900 chromosomes (freq. 0.0003), and South Asian in 48 of 30236 chromosomes (freq. 0.002); it was not seen in the East Asian, African, other, Ashkenazi Jewish, and European Finnish populations. The p.Ser973= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.