ClinVar

Description

The CHEK2 p.Glu84Glu variant was identified in 80 of 2744 proband chromosomes (frequency: 0.03) from families with high risk of HBOC and/or Li-Fraumeni-like syndromes and was present in 43 of 1644 control chromosomes (frequency: 0.03) from healthy individuals (Ingvarsson 2002, Mohamad 2015, Novak 2008, Rashid 2013, Ruijs 2009, Sodha 2002, Staalesen 2004, Kilpivaara 2004, Bayasal 2004). In one study the variant co-occurred with a BRCA2 pathogenic variant (Ingvarsson 2002). The variant was also identified in dbSNP (ID: rs1805129) as “With Likely benign” allele, ClinVar (classified as benign by Ambry Genetics, Prevention Genetics, Counsyl, Color Genomics and Invitae; and likely benign by Illumina), Clinvitae (3x benign and 2x likely benign), Zhejiang Colon Cancer Database (7x) and was not identified in Cosmic database. The variant was identified in control databases in 9839 (265 homozygous) of 276942 chromosomes at a frequency of 0.04 (Genome Aggregation Consortium Feb 27, 2017), identified in the following populations at a frequency greater than 1%: East Asian in 1688 of 18848 chromosomes (freq: 0.09), Ashkenazi Jewish* in 864 of 10150 chromosomes (freq: 0.085), African in 1565 of 23956 chromosomes (freq: 0.065), South Asian in 1209 of 30778 chromosomes (freq: 0.039), Other in 201 of 6450 chromosomes (freq: 0.031), European (Finnish) in 733 of 25778 chromosomes (freq: 0.028), European (Non-Finnish) in 3152 of 126566 chromosomes (freq: 0.025), Latino in 427 of 34416 chromosomes (freq: 0.012) increasing the likelihood this could be a low frequency benign variant. The p.Glu84Glu 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.