Submissions for variant NM_000059.3(BRCA2):c.5350_5351del (p.Asn1784fs) (rs80359507)

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031540	SCV000282406	pathogenic	Breast-ovarian cancer, familial 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000044639	SCV000072652	pathogenic	Hereditary breast and ovarian cancer syndrome	2019-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1784Hisfs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 10923033, 22144684, 21324516, 22006311, 23633455). This variant is also known as 5573delAA and 5578delAA in the literature. ClinVar contains an entry for this variant (Variation ID: 37959). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074537	SCV000108622	pathogenic	not provided	2018-09-11	criteria provided, single submitter	clinical testing	This deletion of two nucleotides is denoted BRCA2 c.5350_5351delAA at the cDNA level and p.Asn1784HisfsX2 (N1784HfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAAAAA[delAA]CACT. The deletion causes a frameshift, changing an Asparagine to a Histidine at codon 1784, and creates a premature stop codon at position 2 of the new reading frame. BRCA2 c.5350_5351delAA is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously denoted as BRCA2 5573delAA or 5578delAA using alternate nomenclature, has been reported in association with breast, ovarian, and prostate cancer (Gayther 1997, Walsh 2011, Zhang 2011, Castro 2013, Cunningham 2014). We consider this variant to be pathogenic.
Ambry Genetics	RCV000131110	SCV000186040	pathogenic	Hereditary cancer-predisposing syndrome	2019-02-26	criteria provided, single submitter	clinical testing	The c.5350_5351delAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides between positions 5350 and 5351 causing a translational frameshift with a predicted alternate stop codon (p.N1784Hfs*2). This mutation is located in the ovarian cancer cluster region (OCCR) of BRCA2 and has been detected in patients from multiple ovarian cancer series to date (Gayther SA et al. Nat. Genet. 1997 Jan;15:103-5; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; George J et al. Clin. Cancer Res. 2013 Jul;19:3474-84). This mutation has also been detected in a prostate cancer patient (Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57) and a male breast cancer patient (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161(3):575-586). Of note, this alteration is also designated as 5573delAA and 5578delAA in published literature. 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.
Michigan Medical Genetics Laboratories,University of Michigan	RCV000031540	SCV000195990	pathogenic	Breast-ovarian cancer, familial 2	2014-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074537	SCV000296699	pathogenic	not provided	2019-07-10	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031540	SCV000327201	pathogenic	Breast-ovarian cancer, familial 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000044639	SCV000591962	pathogenic	Hereditary breast and ovarian cancer syndrome	2014-07-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000044639	SCV000605783	pathogenic	Hereditary breast and ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Asn1784HisfsX2 variant in BRCA2 has been identified in >30 individuals with BRCA2-associated cancers (Gayther 1997, Walsh 2011, Zhang 2011, George 2013, Cunningham 2014, Breast Cancer Information Core (BIC) database, Sharing Clinical Reports Project). This variant has been identified in 1/15316 of European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1784 and leads to a premature termination codon 2 amino acids downstream. This alteration is then 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). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PS4, PM2.
Counsyl	RCV000031540	SCV000677682	pathogenic	Breast-ovarian cancer, familial 2	2015-07-08	criteria provided, single submitter	clinical testing
Color	RCV000131110	SCV000683699	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000044639	SCV000694862	pathogenic	Hereditary breast and ovarian cancer syndrome	2016-05-02	criteria provided, single submitter	clinical testing	Variant summary: The c.5350_5351delAA variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.5386_5387delGA/p.Asp1796fs). One in-silico tool predicts damaging outcome for this variant. This variant is absent in 122212 control chromosomes. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center	RCV000031540	SCV000744468	pathogenic	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031540	SCV000839933	pathogenic	Breast-ovarian cancer, familial 2	2018-02-25	criteria provided, single submitter	clinical testing	This c.5350_5351delAA (p.Asn1784Hisfs*2) frameshift variant in the BRCA2 gene is predicted to introduce a premature translation termination codon and has been reported in multiple unrelated individuals with breast, ovarian, prostate, fallopian, and/or peritoneal cancer (PMID: 8988179, 21324516, 22006311, 23569316, 23633455, 24504028). The c.5350_5351delAA (p.Asn1784Hisfs*2) variant in the BRCA2 gene is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000074537	SCV000883477	pathogenic	not provided	2018-03-13	criteria provided, single submitter	clinical testing	The c.5350_5351delAA; p.Asn1784fs variant (rs80359507) has been identified in multiple patients diagnosed with ovarian, fallopian tube or peritoneal cancer (Gayther 1997, Walsh 2011, Zhang 2011, Cunningham 2014). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37959) and observed in only 1/30754 alleles in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, this variant is considered pathogenic. References: Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014. 4:4026. Gayther S et al. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet. 1997. 15(1):103-5. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.Proc Natl Acad Sci U S A. 2011. 108(44):18032-7. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer.Gynecol Oncol. 2011. 121(2):353-7.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000031540	SCV000993555	pathogenic	Breast-ovarian cancer, familial 2	2018-09-07	criteria provided, single submitter	research
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000031540	SCV001251945	pathogenic	Breast-ovarian cancer, familial 2	2020-05-03	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000074537	SCV001447454	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031540	SCV000054145	pathogenic	Breast-ovarian cancer, familial 2	2012-07-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031540	SCV000146602	pathogenic	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto	RCV000044639	SCV000587763	pathogenic	Hereditary breast and ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen	RCV000031540	SCV000733267	pathogenic	Breast-ovarian cancer, familial 2		no assertion criteria provided	clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic	RCV000074537	SCV000778684	pathogenic	not provided	2017-12-12	no assertion criteria provided	clinical testing