ClinVar Genomic variation as it relates to human health

Observed in individuals with personal or family history of breast cancer (Cavallone 2010); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9247A>G; This variant is associated with the following publications: (PMID: 29394989, 29310832, 12228710, 20694749, 29884841)

The BRCA2 c.9019A>G variant is predicted to result in the amino acid substitution p.Arg3007Gly. This variant has been reported in individuals with breast cancer, however in one study the variant did not segregate with disease within a family and was also found in controls of cohort studies (Cavallone et al. 2010. PubMed ID: 20694749; Apessos et al. 2017. PubMed ID: 29310832; Supplemental File 2 in Lerner-Ellis et al. 2020. PubMed ID: 32885271). A functional study using a protein activity assay found that the p.Arg3007Gly substitution had an intermediate effect (Guidugli et al. 2018. PubMed ID: 29394989). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has interpretations of uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38203/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

The p.R3007G variant (also known as c.9019A>G), located in coding exon 22 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9019. The arginine at codon 3007 is replaced by glycine, an amino acid with dissimilar properties. This alteration was reported in a woman with breast cancer diagnosed at age 47, and it was found to segregate with 2/4 cases of breast cancer in this proband's first degree relatives (Cavallone L et al. Fam. Cancer 2010 Dec;9:507 17). In another study, this alteration was identified in 1/898 Greek breast cancer probands (Apessos A et al. Cancer Genet, 2018 01;220:1-12). This variant was also reported in 1 breast cancer proband in a study of 3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J. et al. J Cancer Res Clin Oncol. 2021 Mar;147(3):871-879) . Two studies utilizing homology-directed DNA repair (HDR) assays both demonstrated this alteration to have intermediate functionality (Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248; Hart SN et al. Genet Med, 2019 01;21:71-80). In addition, this variant was reported as having an intermediate impact by an assay of sensitivity to PARP inhibitors when expressed in a human cell line (Ikegami M. et al. Nat Commun. 2020 05;11(1):2573). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The BRCA2 p.Arg3007Gly variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from French-Canadian individuals or families with hereditary breast cancer; (Cavallone 2010). In this study, the variant did not appear to segregate with disease in the affected family (and DNA was unavailable for further studies). The variant was also identified in dbSNP (ID: rs397507417) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, SCRP (Sharing Clinical Reports Project), and Dept. of Pathology and Molecular Medicine (Queen's University)), Clinvitae (4x), Genesight-COGR (4 clinical labs), LOVD 3.0 (1x), and UMD-LSDB (2x as 3-UV) and was not identified in Cosmic, MutDB, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017) databases. The variant was identified by our laboratory in 1 individual with breast cancer. The p.Arg3007 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Gly variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.