Submissions for variant NM_000059.4(BRCA2):c.7987G>A (p.Glu2663Lys)

dbSNP: rs80359030

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163114	SCV000213624	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-23	criteria provided, single submitter	clinical testing	The p.E2663K variant (also known as c.7987G>A), located in coding exon 17 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7987. The glutamic acid at codon 2663 is replaced by lysine, an amino acid with similar properties. This variant is located in the helical domain of the C-terminal DNA binding domain. This alteration was detected in a patient diagnosed with breast cancer, ovarian cancer, and uterine stromal sarcoma and who had a family history of breast cancer (Miolo G et al. Cancer Biol Ther. 2016 Oct 2;17(10):1017-1021). In addition, this variant segregated with disease in multiple families (Ambry internal data). This alteration was also found deleterious in a homology directed repair assay (Hart SN et al. Genet. Med., 2019 01;21:71-80). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Yang H et al. Science, 2002 Sep;297:1837-48). This amino acid position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001324234	SCV001515180	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-10	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Glu2663 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16489001, 18451181, 18607349, 28339459). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29884841). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function. ClinVar contains an entry for this variant (Variation ID: 52461). This missense change has been observed in individual(s) with breast cancer, ovarian cancer and uterine stromal sarcoma (PMID: 27561088). This variant is present in population databases (rs80359030, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2663 of the BRCA2 protein (p.Glu2663Lys).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811313	SCV002049373	likely pathogenic	not provided	2020-12-30	criteria provided, single submitter	clinical testing	The BRCA2 c.7987G>A; p.Glu2663Lys variant (rs80359030) is reported in the literature in at least one individual affected with breast and ovarian cancer (Miolo 2016). This variant is also reported in ClinVar (Variation ID: 52461), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 2663 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.824). In vitro functional analyses of the variant protein demonstrate reduced homology-directed repair activity (Hart 2019). Additionally, another variants at this codon (c.7988A>T; p.Glu2663Val) has been reported in several families with breast and ovarian cancer and is considered pathogenic (Chenevix-Trench 2006, Rebbeck 2018). Based on available information, the p.Glu2663Lys variant is considered to be likely pathogenic. References: Chenevix-Trench G et al. Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res. 2006 Feb 15;66(4):2019-27. Hart SN et al. Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. Genet Med. 2019 Jan;21(1):71-80. Miolo et al. Association of the germline BRCA2 missense variation Glu2663Lys with high sensitivity to trabectedin-based treatment in soft tissue sarcoma. Cancer Biol Ther. 2016 Oct 2;17(10):1017-1021. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001811313	SCV002551701	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077421	SCV000109219	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-01-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077421	SCV000147241	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000077421	SCV000189902	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354518	SCV001549158	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu2663Lys variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in germline and in sarcoma tissue of a patient with breast, ovarian and a synchronous poorly differentiated stromal uterine sarcoma (Miolo 2016). The auhors felt that patient obtained a complete metabolic response after only 3 cycles of trabectedin treatment, most likely due to presence of this potentially deleterious mutation and the tumor loss of the wild-type BRCA2 allele. The variant was also identified in dbSNP (ID: rs80359030) as "With Pathogenic, Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, SCRP, BIC and Pathway Genomics), Clinvitae, LOVD 3.0 (1x predicted deleterious), and BIC (4x unknown clinical importance). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 1 of 245100 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 1 of 111014 chromosomes (freq: 0.00001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Glu2663 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, two studies calculated protein likelihood ratios and results are in favor of protein loss of function due to the variant (Karchin 2008, Miolo 2016). 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.