Submissions for variant NM_000059.4(BRCA2):c.5569_5573del (p.Glu1857fs)

dbSNP: rs397507788

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000168578	SCV000300892	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.
Ambry Genetics	RCV000167362	SCV000218214	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-24	criteria provided, single submitter	clinical testing	The c.5569_5573delGAAAC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 5569 to 5573, causing a translational frameshift with a predicted alternate stop codon (p.E1857Nfs*2). This alteration was detected in 1/989 unrelated individuals from a cohort of German breast/ovarian cancer families (Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80). 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	RCV000168578	SCV000327230	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	RCV000781141	SCV000919004	pathogenic	Hereditary breast ovarian cancer syndrome	2018-09-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5569_5573delGAAAC (p.Glu1857AsnfsX2) 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. The variant allele was found at a frequency of 8.3e-06 in 120540 control chromosomes (ExAC). The variant, c.5569_5573delGAAAC, has been reported in the literature in at least 3 families affected with Hereditary Breast and Ovarian Cancer (Meindl 2002, Rebbeck 2018). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000781141	SCV001582789	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1857Asnfs*2) 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 and/or family history of breast and/or ovarian cancer (PMID: 11802209, 21990299). This variant is also known as 5797del5bp. ClinVar contains an entry for this variant (Variation ID: 51881). For these reasons, this variant has been classified as Pathogenic.