Submissions for variant NM_000059.4(BRCA2):c.5217_5223del (p.Thr1738_Tyr1739insTer)

dbSNP: rs80359496

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077350	SCV000282401	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044613	SCV000072626	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1739*) 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 present in population databases (rs80359496, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 10717622, 26350514). This variant is also known as 5445del7. ClinVar contains an entry for this variant (Variation ID: 51822). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131077	SCV000186007	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	The c.5217_5223delTTTAAGT (p.Y1739*) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of 7 nucleotides from position 5217 to 5223. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 1739. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/248722) total alleles studied. The highest observed frequency was 0.001% (1/112616) of European (non-Finnish) alleles. This mutation was reported in a woman affected with breast carcinoma (Malone, 2000) and in another family with hereditary breast and ovarian cancer syndrome (Lubinski, 2004). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in 61 families (Heramb, 2018). Of note, this alteration is also designated as 5445del7 in older published literature. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000219434	SCV000278858	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 10717622, 22776961, 26350514, 28888541, 29339979); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5445del7; This variant is associated with the following publications: (PMID: 12649099, 26320393, 23242139, 16086312, 10717622, 15131399, 26295337, 26350514, 15993273, 28152038, 22776961, 29339979, 12698193, 29371908, 30720243, 30787465, 31892343, 31447099, 28888541, 35969835, 36623239)
Color Diagnostics, LLC DBA Color Health	RCV000131077	SCV000292159	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	This variant deletes 7 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 observed in at least six individuals affected with breast and/or ovarian cancer and 2 unaffected individuals, and in suspected hereditary breast and ovarian cancer families (PMID: 10717622, 11710890, 12698193, 21702907, 22776961, 26350514, 33471991; Leiden Open Variation Database DB-ID BRCA2_003626). This variant has been identified in 1/248722 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000219434	SCV000296636	pathogenic	not provided	2022-07-03	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/248722 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 12698193 (2003), 10717622 (2000), 22776961 (2012)) and ovarian cancer (PMID: 26350514 (2015)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077350	SCV000327177	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000219434	SCV000602857	pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing	The BRCA2 c.5217_5223del; p.Tyr1739Ter variant (rs80359496), also known as 5445del7, is reported in the literature in multiple families affected with breast and ovarian cancer syndrome (Malone 2000, Scottish/Northern Irish BRCAI/BRCA2 Consortium 2003). This variant is found on only a single chromosome in the Genome Aggregation Database (1/248722 alleles), indicating it is not a common polymorphism. This variant deletes seven nucleotides and induces an early termination codon, so it 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: Malone KE et al. Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer. 2000 Mar 15;88(6):1393-402. Scottish/Northern Irish BRCAI/BRCA2 Consortium. BRCA1 and BRCA2 mutations in Scotland and Northern Ireland. Br J Cancer. 2003 Apr 22;88(8):1256-62.
Department of Medical Genetics, Oslo University Hospital	RCV000077350	SCV000605664	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044613	SCV000694844	pathogenic	Hereditary breast ovarian cancer syndrome	2021-04-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5217_5223delTTTAAGT (p.Tyr1739X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250156 control chromosomes. c.5217_5223delTTTAAGT has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000077350	SCV000839913	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-27	criteria provided, single submitter	clinical testing	This c.5217_5223del (p.Tyr1739*) variant in exon 11 of the BRCA2 gene is a deletion of seven nucleotides and is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. This particular variant (also published as c.5445del7) has been reported in multiple hereditary breast and ovarian cancer patients (PMID: 10717622, 26350514). The c.5217_5223del variant in the BRCA2 gene is classified as pathogenic.
Revvity Omics, Revvity	RCV000219434	SCV003816145	pathogenic	not provided	2022-08-02	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335076	SCV004046194	pathogenic	BRCA2-related disorder		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 11 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and ovarian cancer (PMID: 10717622, 28888541, 29339979, 30787465, 30720243, 31447099). Loss-of-function variation at the same amino acid residue (p.Tyr1739) has been previously reported in individuals with breast, ovarian, and prostate cancer (PMID: 12872265, 26681312, 32341426, 9150154, 11802209). Loss-of-function variation in BRCA2 is an established mechanism of disease (PMID: 20104584, 20301425). The c.5217_5223del (p.Tyr1739Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/248722) and thus is presumed to be rare. Based on the available evidence, the c.5217_5223del (p.Tyr1739Ter) variant is classified as Pathogenic.
Baylor Genetics	RCV003473359	SCV004210368	pathogenic	Familial cancer of breast	2023-03-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000219434	SCV004226576	pathogenic	not provided	2022-03-15	criteria provided, single submitter	clinical testing	PP5, PM2, PVS1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492355	SCV004240323	pathogenic	Breast and/or ovarian cancer	2023-06-23	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077350	SCV000109147	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-03-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077350	SCV000146571	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044613	SCV000587750	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000077350	SCV000591951	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The c.5217_5223del (p.Tyr1739X) deletion variant has been previously reported in the literature in one of 386 probands with breast carcinoma (Malone 2000). The variant was also reported 14 times in BIC database as having "clinical importance". Several databases including LOVD and UMD also report different variants at the same codon with the same amino acid consequence. This deletion is predicted to cause a frameshift, which leads to a premature stop codon at position 1739. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism for hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.
BRCAlab, Lund University	RCV000077350	SCV002588882	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003335076	SCV004728883	pathogenic	BRCA2-related disorder	2024-02-01	no assertion criteria provided	clinical testing	The BRCA2 c.5217_5223del7 variant is predicted to result in premature protein termination (p.Tyr1739*). This frameshift variant results in a premature termination codon, a nonsense change. This variant has been reported in individual(s) with breast cancer and ovarian cancer (Malone et al 2000. PubMed ID: 10717622; Høberg-Vetti H et al 2015. PubMed ID: 26350514). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51822/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.