Submissions for variant NM_000059.4(BRCA2):c.469_470del (p.Lys157fs)

dbSNP: rs397507739

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077335	SCV000300325	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	RCV000077335	SCV000327068	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000496533	SCV000591685	likely pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000077335	SCV000605637	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565817	SCV000673090	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-21	criteria provided, single submitter	clinical testing	The c.469_470delAA pathogenic mutation, located in coding exon 4 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 469 to 470, causing a translational frameshift with a predicted alternate stop codon (p.K157Vfs*25). This alteration has been reported in multiple individuals and families with a history of breast, ovarian, and/or prostate cancer (Borg A et al. Hum. Mutat. 2010 Mar; 31(3):E1200-40. Adem C et al. Cancer 2003 Jan; 97(1):1-11; van Harssel JJ et al. Fam. Cancer 2010 Jun; 9(2):193-201; Nielsen HR et al. Fam. Cancer 2016 Feb; Hart SN et al. BMJ Open 2016; 6(4):e010332). Of note, this alteration is also designated as 697delAA in the 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.
Color Diagnostics, LLC DBA Color Health	RCV000565817	SCV000683645	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 5 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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000509481	SCV001469426	pathogenic	not provided	2020-03-05	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with prostate cancer, breast cancer, and ovarian cancer in the published literature (PMID: 27084275 (2015), 21553119 (2012), 20104584 (2010)). Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496533	SCV001585122	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys157Valfs*25) 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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is also known as 697delAA. ClinVar contains an entry for this variant (Variation ID: 51698). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000509481	SCV001780633	pathogenic	not provided	2022-12-01	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 697_698delAA; This variant is associated with the following publications: (PMID: 20104584, 12491499, 27084275, 29339979, 29566657, 29446198, 26833046, 32665702, 21553119, 19949876)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000509481	SCV002550251	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496533	SCV002570763	pathogenic	Hereditary breast ovarian cancer syndrome	2022-07-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.469_470delAA (p.Lys157ValfsX25) 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 was absent in 251040 control chromosomes. c.469_470delAA has been 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. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) 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.
Baylor Genetics	RCV003473346	SCV004212779	pathogenic	Familial cancer of breast	2022-06-09	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000077335	SCV005046002	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM2_supporting; PM5_PTC_Strong
Sharing Clinical Reports Project (SCRP)	RCV000077335	SCV000109132	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-05-10	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496533	SCV000587550	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000509481	SCV000607255	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000509481	SCV001906333	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000509481	SCV001959658	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000509481	SCV001965782	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077335	SCV004243803	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004542697	SCV004778560	pathogenic	BRCA2-related disorder	2024-01-05	no assertion criteria provided	clinical testing	The BRCA2 c.469_470delAA variant is predicted to result in a frameshift and premature protein termination (p.Lys157Valfs*25). This variant was reported in an individual with breast and prostate cancers (described as c.697delAA, Adem. 2003. PubMed ID: 12491499; Hart. 2016. PubMed ID: 27084275). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted in ClinVar as pathogenic and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/51698/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.