Submissions for variant NM_000059.4(BRCA2):c.6446_6450del (p.Ile2149fs)

dbSNP: rs80359593

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077376	SCV000301049	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000044955	SCV000072968	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile2149Serfs*25) 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 and/or ovarian cancer (PMID: 15131399, 20858050). ClinVar contains an entry for this variant (Variation ID: 52102). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162931	SCV000213418	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-11	criteria provided, single submitter	clinical testing	The c.6446_6450delTTAAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 6446 to 6450, causing a translational frameshift with a predicted alternate stop codon (p.I2149Sfs*25). This pathogenic mutation has been reported in individuals with HBOC-related cancers (Lubinski J et al. Fam. Cancer. 2004;3(1):1-10; Dworkin AM et al. Fam. Cancer 2009 Apr;8(4):339-46; Foley SB et al. EBioMedicine 2015 Jan;2(1):74-81), and in Japanese breast cancer cohorts (Nakamura S et al. Breast Cancer 2015 Sep;22(5):462-8; Kwong A et al. J. Med. Genet. 2016 Jan;53(1):15-23; Momozawa Y et al. Nat. Commun. 2018 10;9(1):4083). Of note, this alteration is also designated as 6674del5 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077376	SCV000327431	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044955	SCV000917057	pathogenic	Hereditary breast ovarian cancer syndrome	2021-03-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6446_6450delTTAAA (p.Ile2149SerfsX25) 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 230326 control chromosomes. c.6446_6450delTTAAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Coulet_2010, Dworkin_2009, Nakamura_2013, Lubinski_2004, Kanke_2018, Kwong_2015). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories, one expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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	RCV000162931	SCV001342837	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001582541	SCV001473221	pathogenic	not provided	2019-08-05	criteria provided, single submitter	clinical testing	The BRCA2 c.6446_6450delTTAAA; p.Ile2149fs variant (rs80359593), also known as 6674del5, is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancers (Dworkin 2009, Kanke 2017, Kwong 2016, Lubinski 2004, Nakamura 2015). This variant is reported in ClinVar (Variation ID: 52102), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several other downstream truncating variants have been reported in individuals with breast and ovarian cancers and are considered pathogenic Kwong 2016, Lubinski 2004, Nakamura 2015). Based on available information, this variant is considered to be pathogenic. References: Dworkin AM et al. Methylation not a frequent "second hit" in tumors with germline BRCA mutations. Fam Cancer. 2009;8(4):339-46. Kanke Y et al. Gene aberration profile of tumors of adolescent and young adult females. Oncotarget. 2017 Dec 29;9(5):6228-6237. Kwong A et al. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries. J Med Genet. 2016 Jan;53(1):15-23. Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. Nakamura S et al. Prevalence and differentiation of hereditary breast and ovarian cancers in Japan. Breast Cancer. 2015 Sep;22(5):462-8.
GeneDx	RCV001582541	SCV001820107	pathogenic	not provided	2020-10-01	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 BRCA2-related cancers (Lubinksi 2004, Dworkin 2009, Foley 2015, Nakamura 2015, Kanke 2018, Momozawa 2018); 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 6445_6449del5, 6674del5, or 6674_6678delTTAAA; This variant is associated with the following publications: (PMID: 31214711, 29176636, 19340607, 20858050, 24249303, 26023681, 26187060, 29464067, 30287823, 15131399)
Fulgent Genetics, Fulgent Genetics	RCV002490605	SCV002800309	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-03-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473378	SCV004212855	pathogenic	Familial cancer of breast	2022-01-21	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077376	SCV000109173	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077376	SCV000146857	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044955	SCV000587849	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research