Submissions for variant NM_000059.4(BRCA2):c.5557dup (p.Cys1853fs)

dbSNP: rs587782011

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)	RCV000661693	SCV000783997	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.
GeneDx	RCV000373216	SCV000330693	pathogenic	not provided	2016-07-26	criteria provided, single submitter	clinical testing	The c.5557dupT pathogenic variant in the BRCA2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.5557dupT variant causes a frameshift starting with codon Cysteine 1853, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Cys1853LeufsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.5557dupT variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.5557dupT as an expected pathogenic variant.
GeneKor MSA	RCV000373216	SCV000821713	pathogenic	not provided	2021-01-09	criteria provided, single submitter	clinical testing	This variant is a single base pair insertion in exon 11 of the BRCA2 mRNA, causing a frameshift after codon 1853 and this creates a premature translational stop signal 5 amino acid residues later. This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 280750).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064092	SCV001228968	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 280750). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 30720863). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys1853Leufs*5) 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).
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001642882	SCV001852772	pathogenic	Breast carcinoma	2021-09-12	no assertion criteria provided	clinical testing