Submissions for variant NM_000059.4(BRCA2):c.8754G>A (p.Glu2918=)

dbSNP: rs80359803

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131042	SCV000185972	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-24	criteria provided, single submitter	clinical testing	The c.8754G>A pathogenic variant (also known as p.E2918E), located in coding exon 20 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8754. This nucleotide substitution does not change the glutamic acid at codon 2918. However, this change occurs in the last base pair of coding exon 20, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in numerous breast cancer cohorts (Finkelman BS et al. J. Clin. Oncol., 2012 Apr;30:1321-8; Kaur RP et al. Med. Oncol., 2018 Apr;35:81; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Millan Catalan O et al. Cancers (Basel), 2019 Aug;11:). Multiple different RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Acedo A et al. Hum. Mutat., 2015 Feb;36:210-21). In addition, many other non-canonical splice alterations have been identified at this donor site and are also known to lead to a complete aberrant splice defect (Colombo M et al. PLoS One, 2013 Feb;8:e57173; Brandão RD et al. Breast Cancer Res Treat, 2011 Oct;129:971-82; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14; Bonatti F et al. Cancer Genet Cytogenet, 2006 Oct;170:93-101; Houdayer C et al. Hum Mutat, 2012 Aug;33:1228-38; Acedo A et al. Hum Mutat, 2015 Feb;36:210-21; Hendriks G et al. Hum Mutat, 2014 Nov;35:1382-91). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077451	SCV000327958	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000523204	SCV000619052	likely pathogenic	not provided	2017-07-13	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8754G>A at the DNA level. Although the variant is silent at the codinglevel, preserving a Glutamic Acid at codon 2918, it has been demonstrated to cause abnormal splicing. Located at thelast nucleotide of exon 21, it disrupts a natural splice donor site and was found to cause abnormal splicing wheninterrogated via minigene assay (Acedo 2014). This variant, also reported as BRCA2 8982G>A using alternatenomenclature, has been published in at least one individual reported to have Hereditary Breast and Ovarian Cancersyndrome (Finkelman 2012). In addition, nearby variants found to cause the same impact on splicing have beenreported in association with Hereditary Breast and Ovarian Cancer (Brandão 2011). BRCA2 c.8754G>A was notobserved in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek2016). The nucleotide which is altered, a guanine (G) at base 8754, is conserved across species. Based on currentlyavailable information, we consider BRCA2 c.8754G>A to be likely pathogenic
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000523204	SCV001133947	likely pathogenic	not provided	2022-10-27	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. The frequency of this variant in the general population, 0.000004 (1/250952 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with breast cancer (PMID: 29700634 (2018), 31454914 (2019)). It was also identified in individuals at-risk for breast/ovarian cancer (PMID: 22430266 (2012), 29446198 (2018)). Additionally, the authors of an in vitro minigene study observed that the variant abrogated the splice site completely and inserted noncoding sequence from the intron, including a premature stop codon, into the mRNA (PMID: 25382762 (2015)). Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496546	SCV001576245	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-07	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs80359803, gnomAD 0.003%). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25382762). ClinVar contains an entry for this variant (Variation ID: 52671). This variant is also known as E2918E. This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22430266, 24145998, 29700634, 31454914). This sequence change affects codon 2918 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496546	SCV002819555	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8754G>A (p.Glu2918Glu) alters the conserved last nucleotide of exon 21 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, leading to a shift in the reading frame (Acedo_2015). The variant allele was found at a frequency of 4e-06 in 250952 control chromosomes. c.8754G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Sambiasi_2014 Kaur_2018, Rebbeck_2018, Finkelman_2012). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496546	SCV004848891	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-15	criteria provided, single submitter	clinical testing	The p.Glu2918Glu variant in BRCA2 has been reported in at least 13 individuals with BRCA2-associated cancers, including at least 1 male with breast cancer, and segregated with disease in 2 affected relatives from 1 family (Kaur 2018 PMID: 29700634, Millan Catalan 2019 PMID: 31454914, Bapat 2021 medRxiv 2021.07.01.21258680; doi: https://doi.org/10.1101/2021.07.01.21258680). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 52671) and was absent from large population studies. Although it is a synonymous (silent) variant, it is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools predict a splicing impact, which is corroborated by an in vitro minigene assay that indicates that this synonymous change disrupts normal splicing and results in an aberrant transcript that is subjected to nonsense-mediated decay (Acedo 2015 PMID: 25382762). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer (HBOC). ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PS3_Supporting.
Sharing Clinical Reports Project (SCRP)	RCV000077451	SCV000109249	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-04-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077451	SCV000147451	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2000-11-10	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496546	SCV000587968	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research