Submissions for variant NM_000059.4(BRCA2):c.5569G>T (p.Glu1857Ter)

dbSNP: rs80358778

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113444	SCV000300891	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113444	SCV000327231	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496399	SCV001365928	pathogenic	Hereditary breast ovarian cancer syndrome	2019-02-08	criteria provided, single submitter	clinical testing	The p.Glu1857X variant in BRCA2 has been previously reported in at least 4 individuals with BRCA2-associated cancers (Breast Information Core Database (BIC): https://research.nhgri.nih.gov/bic/) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1857 which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). Moreover, this variant was classified as pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300891.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein, absence from the general population and presence in multiple affected individuals. ACMG/AMP Criteria applied: PVS1, PM2, PS4_supporting.
Invitae	RCV000496399	SCV001590568	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1857*) 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 personal and/or family history of breast and/or ovarian cancer (PMID: 10995809, 29446198). This variant is also known as 5797G>T. ClinVar contains an entry for this variant (Variation ID: 51880). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002345335	SCV002650897	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-23	criteria provided, single submitter	clinical testing	The p.E1857* pathogenic mutation (also known as c.5569G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 5569. This changes the amino acid from a glutamic acid to a stop codon within coding exon 10. This alteration was observed in 2 of 1035 consecutive, newly diagnosed breast cancer patients with a family history of breast and/or ovarian cancer within a Finnish cohort (Syrjäkoski K et al. J Natl Cancer Inst, 2000 Sep;92:1529-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492357	SCV004240328	pathogenic	Breast and/or ovarian cancer	2023-04-24	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113444	SCV000146634	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496399	SCV000587773	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research