Submissions for variant NM_000059.4(BRCA2):c.426-12_426-8del

dbSNP: rs276174844

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203666	SCV000072393	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000044380	SCV000210806	uncertain significance	not provided	2024-02-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate aberrant splicing leading to skipping of exon 5 resulting in a truncated BRCA2 protein, but also show the presence of wild-type transcript indicating an incomplete splice defect (PMID: 19070627, 20215541, 21394826, 30883759); Observed in individuals with a personal and/or family history of BRCA2-related cancers, some of whom also carried a pathogenic variant in BRCA1 or BRCA2, and reported to occur in trans with a pathogenic BRCA2 variant in individuals without known features of Fanconi anemia (PMID: 18446624, 19070627, 26681312, 30675319, 35050751); Not observed at significant frequency in large population cohorts (gnomAD); Also known as BRCA2 654-12_654-8delGTTTT and IVS4-12del5; This variant is associated with the following publications: (PMID: 27060066, 30675319, 31642931, 23893897, 16162645, 20215541, 21394826, 19070627, 32133419, 31131967, 18446624, 24212087, 31980526, 30883759, 10923033, 26681312, 21520333, 35050751)
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113566	SCV000744382	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496561	SCV000919003	uncertain significance	not specified	2023-06-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.426-12_426-8delGTTTT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Two computational tools predict the variant weakens a 3' acceptor site. In addition, a recent computational study predicted a high probability of splicing impact (Leman_2018). Several publications reported experimental evidence that this variant affects mRNA splicing, by increasing exon 5 skipping (predicted to result in a frameshift), and consequently decreasing the expression of the full-length transcript (e.g., Zhang_2009, Sanz_2010, Whiley_2011, Whiley_2014, Lattimore_2018, Fraile-Bethencourt_2019). However, a more recent study found that this aberrant splicing is inefficient and the percent splicing index (PSI) was determined to be ~20% in positive controls (vs. ~10% in healthy controls) (Landrith_2020); the amount of normal transcript needed for normal BRCA2 function is unknown (Nix_2020). The variant was absent in 249586 control chromosomes (gnomAD). c.426-12_426-8delGTTTT has been reported in the literature in individuals affected with breast cancer, as well as unaffected individuals (e.g., Zhang_2009, Whiley_2011, Susswein_2015). These reports do not allow any conclusion about variant significance. Multiple co-occurrences with other pathogenic variants have been reported (BRCA2 c.9257-1G>C [NHGRI BIC database, Nix_2020]; BRCA2 c.7248del, p.H2417TfsX50 [LOVD database]; BRCA1 c.5152+1G>T [Loughrey_2008]; BRCA2 c.7719dupA, p.W2574MfsX10 [Nix_2020]), providing supporting evidence for a benign role. Particularly, Nix et al (2020) report carriers of the variant did not have a personal or family history consistent with pathogenicity and they specify that the variant was found to co-occur in trans with two different pathogenic variants in BRCA2 in individuals with no known features of Fanconi anemia. The following publications have been ascertained in the context of this evaluation (PMID: 26992833, 27060066, 30675319, 30883759, 21702907, 31642931, 29774201, 29750258, 18446624, 20215541, 26681312, 24212087, 21394826, 19070627, 32133419, 35050751). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014; 7 submitters classified the variant as VUS, and 1 submitter classified it as likely benign. Based on the evidence outlined above, the variant was re-classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044380	SCV001133786	uncertain significance	not provided	2019-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022168	SCV001183869	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-20	criteria provided, single submitter	clinical testing	The c.426-12_426-8delGTTTT intronic variant, results from a deletion of 5 intronic nucleotides upstream of coding exon 4 in the BRCA2 gene. This alteration, designated as IVS4-12del5, was identified in a family with melanoma, breast and pancreatic cancer and segregated with disease in this family. Furthermore, a breast tumor from this family showed loss of heterozygosity for BRCA2 (Zhang L et al. Mutat. Res. 2009 Apr;663:84-9). This variant has been shown to cause incomplete exon skipping, leading to a frameshift and creation of a premature alternative stop codon (Zhang L et al. Mutat. Res. 2009 Apr;663:84-9; Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; Whiley PJ et al. Hum. Mutat. 2011 Jun;32:678-87; Whiley PJ et al. Clin. Chem. 2014 Feb;60:341-52). In addition, internal, quantitative RNA studies have demonstrated this alteration results in a substantial amount of abnormal splicing. However, this alteration has also been reported in trans with other pathogenic BRCA2 variants in patients of unknown age and phenotype who do not have overt symptoms of Fanconi Anemia (Ambry internal data; Nix, P et al. JCO Prec. Onc. 2020 June;4:790-35). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001022168	SCV001339313	uncertain significance	Hereditary cancer-predisposing syndrome	2020-05-27	criteria provided, single submitter	clinical testing	This variant causes a deletion of 5 nucleotides in intron 4 of the BRCA2 gene. The variant is also known as IVS4-12del5, c.654-12_654-8delGTTTT, and c.426-12_8del5 in the literature. Experimental RNA studies of this variant have demonstrated a partial impact on splicing, increasing the skipping of exon 5 and producing a truncated protein in mutant cells (PMID: 19070627, 20215541, 21394826, 24212087, 30883759, 32133419). However, significant baseline expression of the exon 5 skipped transcript in normal cells may limit the variant's causal impact on disease (PMID: 27060066, 29774201, 32133419). This variant has been reported in individuals affected with breast cancer in the literature, but also in unaffected individuals (PMID: 10923033, 18446624, 19070627, 30675319, 16162645). This variant has also been observed to co-occur with pathogenic variants in BRCA1 (PMID: 18446624, Color Internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000044380	SCV001747693	uncertain significance	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001022168	SCV002533861	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	curation
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000203666	SCV005184338	likely benign	Hereditary breast ovarian cancer syndrome	2024-04-09	criteria provided, single submitter	curation	According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PM2 (supporting pathogenic): absent from controls (gnomAD v2/3), PP3 (supporting pathogenic): SpliceAI ≥ 0.2, BP5 (medium benign): Combined LR (Parsons 2019): 0.1359 (cutoff 0.23:1<LR<0.05:1), BS2 (medium benign): Nix 2020 (PMID: 35050751): in 2 individuals with no known features of Fanconi anemia confirmed in trans with BRCA2 c.7719dupA or c.9257-1G>C
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113566	SCV000146817	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496561	SCV000587547	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000113566	SCV000733210	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing