Submissions for variant NM_000059.4(BRCA2):c.1773_1776del (p.Ile591fs)

dbSNP: rs80359304

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112966	SCV000282360	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.
Invitae	RCV000043880	SCV000071893	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile591Metfs*22) 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 cancer (PMID: 12942367, 18393245, 22923021). This variant is also known as 2001delTTAT. ClinVar contains an entry for this variant (Variation ID: 51190). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000160268	SCV000210715	pathogenic	not provided	2022-09-15	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Kanaan et al., 2003; Thirthagiri et al., 2008; Novakovic et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2001_2004del; This variant is associated with the following publications: (PMID: 18393245, 28993434, 32846166, 30787465, 31825140, 32719484, 26295337, 20104584, 12942367, 28439188, 28888541, 29446198, Bahsi2020[case report], 30702160, 24123850, 30875412, 18627636, 22923021)
Ambry Genetics	RCV000213388	SCV000274783	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-30	criteria provided, single submitter	clinical testing	The c.1773_1776delTTAT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1773 to 1776, causing a translational frameshift with a predicted alternate stop codon (p.I591Mfs*22). This mutation has been detected in multiple individuals from hereditary breast and/or ovarian cancer cohorts also unselected breast cancer cohorts (Kanaan Y et al. Hum. Genet. 2003 Oct;113:452-60; Thirthagiri E et al. Breast Cancer Res. 2008 Jul;10:R59; Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Yildiz T et al. Life Sci 2020 Nov;261:118334; Demir S et al. J BUON;25(3):1337-1347). Of note, this mutation is also designated as 2001del4 in published literature. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000112966	SCV000296721	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-02-25	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112966	SCV000326608	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000112966	SCV000677670	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000160268	SCV001450407	pathogenic	not provided	2018-10-22	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310171	SCV001499766	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043880	SCV001623181	pathogenic	Hereditary breast ovarian cancer syndrome	2021-04-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1773_1776delTTAT (p.Ile591MetfsX22) 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. The variant was absent in 248932 control chromosomes. c.1773_1776delTTAT has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, a consortium (CIMBA) and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000213388	SCV002052184	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2001del4 and 2000del4 in the literature according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least four individuals affected with breast cancer (PMID: 12942367, 18393245, 18627636, 20174566, 33471991) and in suspected hereditary breast and ovarian cancer families (PMID: 19949876, 21120943, 22923021). 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.
Baylor Genetics	RCV003460563	SCV004216170	pathogenic	Familial cancer of breast	2023-05-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160268	SCV004242827	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112966	SCV000145930	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112966	SCV000145931	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	RCV000043880	SCV000587609	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000160268	SCV001550959	uncertain significance	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112966	SCV004244227	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing