Submissions for variant NM_000059.4(BRCA2):c.5653del (p.Cys1885fs)

dbSNP: rs886040602

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000576752	SCV000783695	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-15	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476395	SCV000549617	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-23	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys1885Alafs*24) 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 has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 409491). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000576752	SCV000677898	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000476395	SCV000918877	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-11-03	criteria provided, single submitter	clinical testing	Variant summary: The c.5653delT (p.Cys1885Alafs*24) variant in BRCA2 gene is a frameshift change that results in the loss of the ~1500 amino acids of BRCA2 protein (~55%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population datasets of ExAC and gnomAD (120680 and 244700 chrs tested, respectively). The c.5653delT has not, to our knowledge, been reported in affected individuals via published reports but is cited as Pathogenic by reputable databases/clinical laboratories. Other truncated variants, such as c.5656C>T (p.Gln1886* and c.5665delA (p.Ile1889Leufs*20), have been reported in association with HBOC. Taking together, the variant was classified as Likely Pathogenic.