Submissions for variant NM_000059.4(BRCA2):c.5645C>G (p.Ser1882Ter)

dbSNP: rs80358785

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113452	SCV000300911	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	RCV000113452	SCV000327252	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568762	SCV000668525	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-05	criteria provided, single submitter	clinical testing	The p.S1882* pathogenic mutation (also known as c.5645C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 5645. This changes the amino acid from a serine to a stop codon within coding exon 10. This pathogenic mutation has been reported in an ovarian cancer patient, and was confirmed in a formalin-fixed paraffin-embedded (FFPE) tumor tissue sample to show loss of heterozygosity (LOH) (Weren RD et al. Hum. Mutat. 2017 Feb;38:226-235). Further, an alteration resulting in the same truncated protein, p.S1882* (c.5645C>A), has been reported in an individuals diagnosed with triple negative breast cancer, ovarian cancer, and in a family with multiple cases of breast cancer (Meyer P et al. PLoS One 2012;7(5):e38361; Sakomoto I et al. Cancer 2016 Jan;122(1):84-90; Verhoog LC et al. J. Clin. Oncol. 1999 Nov;17(11):3396-3402). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284577	SCV001470435	pathogenic	not provided	2019-12-18	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496664	SCV001588950	pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 9346). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 19949876, 22666503, 27767231, 28039656, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1882*) 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).
OMIM	RCV000009937	SCV000030158	pathogenic	Wilms tumor 1	2005-02-01	no assertion criteria provided	literature only
OMIM	RCV000009938	SCV000030159	risk factor	Glioma susceptibility 3	2005-02-01	no assertion criteria provided	literature only
OMIM	RCV000009939	SCV000030160	pathogenic	Medulloblastoma	2005-02-01	no assertion criteria provided	literature only
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113452	SCV000146654	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	RCV000496664	SCV000587785	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001284577	SCV001959642	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001284577	SCV001972096	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000113452	SCV004243680	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing