Submissions for variant NM_000059.4(BRCA2):c.4712_4713del (p.Glu1571fs)

dbSNP: rs80359464

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)	RCV000031500	SCV000282395	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000164613	SCV000215276	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-07	criteria provided, single submitter	clinical testing	The c.4712_4713delAG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4712 to 4713, causing a translational frameshift with a predicted alternate stop codon (p.E1571Gfs*3). This mutation has been reported in multiple individuals with breast and/or ovarian cancer (Rebbeck TR et al. Hum. Mutat. 2018 May;39:593-620; Kalachand RD et al. Obstet Gynecol Sci, 2020 09;63:643-654; Dorling et al. N Engl J Med. 2021 02;384:428-439), as well as in 1/3579 men of African ancestry with prostate cancer (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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.
GeneDx	RCV000213951	SCV000279271	pathogenic	not provided	2023-05-22	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Also known as 4940_4941delAG, 4936delAG, and c.4708_4709del; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Lancaster et al., 1996; Young et al., 2009; Lilyquist et al., 2017; Rebbeck et al., 2018; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 19298662, 8640235, 21702907, 27221827, 33471991, 32832836, 32872764, 28888541, 29446198)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031500	SCV000327074	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213951	SCV000600603	pathogenic	not provided	2023-05-17	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in an individual with ovarian cancer (PMID: 32832836 (2020)). Additionally, in a large-scale breast cancer association study, the variant was observed in individuals with breast cancer (PMID: 33471991 (2021), ). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000164613	SCV000683647	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-22	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 8640235, 19298662, 32614418) and ovarian cancer (PMID: 32872764). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000257921	SCV000694798	pathogenic	Hereditary breast ovarian cancer syndrome	2016-01-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000257921	SCV001386072	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1571Glyfs*3) 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 breast cancer (PMID: 8640235, 19298662, 21702907). This variant is also known as c.4940_4941delAG, c.4710delAG and c.4936delAG. ClinVar contains an entry for this variant (Variation ID: 37919). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149597	SCV003838160	pathogenic	Breast and/or ovarian cancer	2022-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473179	SCV004210388	pathogenic	Familial cancer of breast	2023-12-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031500	SCV000054105	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2009-08-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031500	SCV000146473	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000257921	SCV000587721	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research