Submissions for variant NM_000059.4(BRCA2):c.891_899delinsGATACTTCAG (p.Thr298fs)

dbSNP: rs276174914

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112859	SCV000783805	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-15	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000160265	SCV000210709	pathogenic	not provided	2020-10-13	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Malone 2006, Susswein 2016); Also known as 1119del9ins10; This variant is associated with the following publications: (PMID: 16912212, 26681312)
Ambry Genetics	RCV000218535	SCV000277017	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-13	criteria provided, single submitter	clinical testing	The c.891_899delAACAGTTGTins10 variant, located in coding exon 9 of the BRCA2 gene, results from the deletion of 9 nucleotides and insertion of 10 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.T298Ifs*7). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461715	SCV000549682	pathogenic	Hereditary breast ovarian cancer syndrome	2018-03-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr298Ilefs*7) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with breast cancer (PMID: 26681312), as well as several individuals in the Breast Cancer Information Core database (PMID: 10923033). This variant is also known as c.891_899delAACAGTTGTinsGATACTTCAG in the literature. ClinVar contains an entry for this variant (Variation ID: 125928). A different variant (c.893_899delCAGTTGTinsTACTTCAG) giving rise to the same protein effect observed here (p.Thr298Ilefs*7) has been reported in an individual affected with breast and ovarian cancer (PMID: 27798748), indicating that this residue may be critical for protein function. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Molecular Medicine, Queen's University	RCV000461715	SCV000588073	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769683	SCV000901096	pathogenic	Breast and/or ovarian cancer	2017-05-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000218535	SCV000905001	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant is located in the BRCA2 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000461715	SCV000918927	pathogenic	Hereditary breast ovarian cancer syndrome	2018-06-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.891_899delinsGATACTTCAG (p.Thr298IlefsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg., p.Asn319fsX8 and p.Lys343fsX6). The variant was absent in 235816 control chromosomes. c.891_899delinsGATACTTCAG has been reported in the literature and reputable databases in individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160265	SCV001133954	pathogenic	not provided	2024-06-12	criteria provided, single submitter	clinical testing	The BRCA2 c.891_899delinsGATACTTCAG (p.Thr298Ilefs*7) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 26681312 (2015), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV003474694	SCV004210466	pathogenic	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112859	SCV000145784	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000461715	SCV000587574	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research