Submissions for variant NM_000059.4(BRCA2):c.7762_7764delinsTT (p.Ile2588fs)

dbSNP: rs483353072

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)	RCV000225480	SCV000282449	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000222283	SCV000277871	pathogenic	Hereditary cancer-predisposing syndrome	2015-08-12	criteria provided, single submitter	clinical testing	The c.7762_7764delinsTT(also known as 7990delATAinsTT)pathogenic mutation, located in coding exon 15 of the BRCA2 gene, results from the deletion of threenucleotides and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon. This alteration has been previously identified in one family with HBOC(Evans DG, J. Med. Genet. 2003 Sep; 40(9):e107.). In addition to the clinical history presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).<br />
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254816	SCV000296731	pathogenic	not provided	2020-11-06	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals and families with hereditary breast and/or ovarian cancer (PMIDs: 12960223 (2003), 18703817 (2008), 18824701 (2008), 20104584 (2010)) and pancreatic cancer (PMID: 30274973 (2018)). 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.
GeneDx	RCV000254816	SCV000322114	pathogenic	not provided	2020-08-11	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; Also known as 7990del3ins2 or 7990delATAinsTT; This variant is associated with the following publications: (PMID: 25685387, 27181684, 12960223, 20104584, 24307375, 23242139, 22706548, 18703817, 15131399, 26295337, 30274973, 31447099)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000225480	SCV000327726	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV000476038	SCV000549642	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile2588Phefs*60) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast, ovarian or pancreatic cancer (PMID: 12960223, 15131399, 20104584, 30274973). This variant is also known as 7990delATAinsTT and 7990del3ins2. ClinVar contains an entry for this variant (Variation ID: 233493). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000476038	SCV000605779	pathogenic	Hereditary breast ovarian cancer syndrome	2016-06-02	criteria provided, single submitter	clinical testing	The p.Ile2588fs (c.7762_7764delinsTT) variant in BRCA2 has been reported in at l east 8 individuals with BRCA2-associated cancers (Evans 2003, Lai 2015, Breast C ancer Information Core database, www.research.nhgri.nih.gov/bic/). While this va riant was absent from large population studies, the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a fr ameshift, which alters the protein?s amino acid sequence beginning at position 2 588 and leads to a premature termination codon 60 amino acids downstream. This a lteration is then predicted to lead to a truncated or absent protein. Heterozygo us loss of function of the BRCA2 gene is an established disease mechanism in her editary breast and ovarian cancer (HBOC). Additionally, the p.Ile2588fs variant has been classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIG MA Expert Panel (ClinVar SCV000282449.1). In summary, this variant meets our cri teria to be classified as pathogenic for HBOC in an autosomal dominant manner ba sed upon the predicted impact to the protein and presence in multiple affected i ndividuals.
Color Diagnostics, LLC DBA Color Health	RCV000222283	SCV000689066	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This variant deletes 3 nucleotides and inserts 2 nucleotides in exon 16 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 7990delATAinsTT or 7990del3ins2 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 5 individuals affected with pancreatic, breast, or ovarian cancer (PMID: 18824701, 20104584, 24307375, 30274973). 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	RCV000476038	SCV000918917	pathogenic	Hereditary breast ovarian cancer syndrome	2018-06-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7762_7764delinsTT (p.Ile2588PhefsX60) 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.Trp2626X, p.Met2634fsX14, and p.Arg2645fsX3). The variant was absent in 246218 control chromosomes (gnomAD). The variant, c.7762_7764delinsTT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Evans_2003, Lai_2015, Watson_2014, Borg_2010, Spearman_2008, Palma_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003475032	SCV004210522	pathogenic	Familial cancer of breast	2022-08-05	criteria provided, single submitter	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000476038	SCV000587908	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354519	SCV001549159	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ile2588Phefs*60 variant was identified in 2 of 5068 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer (Borg 2010, Evans 2003). The variant was also identified in ClinVar (classified as pathogenic by ENIGMA expert panel, Invitae, GeneDx, Ambry Genetics and six other submitters). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.7762_7764delinsTT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2588 and leads to a premature stop codon at position 2647. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer (HBOC) and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.