Submissions for variant NM_000059.4(BRCA2):c.5641_5644del (p.Lys1881fs)

dbSNP: rs276174860

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113451	SCV000282409	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.
GeneDx	RCV000235141	SCV000108627	pathogenic	not provided	2021-08-25	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; 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 of breast and ovarian cancer (Machackova 2008, Tea 2014, Couch 2015, Marlin 2020); Not observed at significant frequency in large population cohorts (Lek 2016); Also known as 5869_5872del; This variant is associated with the following publications: (PMID: 25452441, 29907814, 32040869, 22762150, 24549055, 12181777, 23884708, 24156927, 18489799)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113451	SCV000327250	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509599	SCV000607777	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-03	criteria provided, single submitter	clinical testing	The c.5641_5644delAAAT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides between nucleotide positions 5641 and 5644, causing a translational frameshift with a predicted alternate stop codon (p.K1881Qfs*27). This alteration has been previously reported in numerous breast and/or ovarian cancer cohorts (Liede A et al. Am. J. Hum. Genet. 2002 Sep;71(3):595-606; Machackova E et al. BMC Cancer 2008;8:140; Tea MK et al. Maturitas 2014 Jan;77(1):68-72; Couch FJ et al. J. Clin. Oncol. 2015 Feb; 33(4):304-11; Palmero E et al. Sci. Rep. 2018 Jun;8(1):9188). Of note, this alteration is also designated 5869delAAAT in the 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.
Color Diagnostics, LLC DBA Color Health	RCV000509599	SCV000903718	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-25	criteria provided, single submitter	clinical testing	This variant deletes 4 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 12181777, 23884708, 24156927, 24549055, 25452441). 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	RCV001192483	SCV001360638	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5641_5644delAAAT (p.Lys1881GlnfsX27) 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 249328 control chromosomes. c.5641_5644delAAAT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is very likely to be associated with disease. Five 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001192483	SCV001588949	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1881Glnfs*27) 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 a personal or family history of breast and/or ovarian cancer (PMID: 12181777, 18489799, 23884708, 24549055, 25452441, 29907814). This variant is also known as c.5869_5872del4 and 5869delAAAT. ClinVar contains an entry for this variant (Variation ID: 51897). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113451	SCV000146652	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-12-17	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV001271040	SCV001451858	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000113451	SCV004243678	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing