Submissions for variant NM_000059.4(BRCA2):c.470_474del (p.Lys157fs)

dbSNP: rs80359463

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077336	SCV000282394	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	RCV000131856	SCV000186911	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-04	criteria provided, single submitter	clinical testing	The c.470_474delAGTCA pathogenic mutation, located in coding exon 4 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 470 to 474, causing a translational frameshift with a predicted alternate stop codon (p.K157Sfs*24). In addition to causing premature protein truncation, functional splicing analysis demonstrates that this alteration also results in exon 5 skipping via disruption of the exonic splicing enhancer (Sanz DJ et al. Clin. Cancer Res. 2010; 16:1957-67). This alteration was previously reported in one individual with breast cancer at age 32 from a Chinese cohort of 489 breast cancer patients with a diagnosis under the age of 35 or a family history of breast and/or ovarian cancer ( Li WF et al. Breast Cancer Res. Treat. 2008; 110:99-109). 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	RCV000077336	SCV000296737	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-02-05	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077336	SCV000327070	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	RCV000496831	SCV000591686	pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131856	SCV000683646	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides in exon 5 of the BRCA2 protein, 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 11 individuals affected with breast or ovarian cancer (PMID: 17851763, 28294317, 29487695, 31174498, doi:10.1515/tjb-2019-0424) and has been identified in 5 families among the CIMBA participants (PMID: 29446198). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496831	SCV001588434	pathogenic	Hereditary breast ovarian cancer syndrome	2022-12-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown this premature translational stop signal is associated with skipping of exon 5, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 20215541, 27060066). ClinVar contains an entry for this variant (Variation ID: 51701). This variant is also known as 698del5, Stop 180, c.469_473del. This premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 17851763, 27767231, 28294317, 28724667, 29487695). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys157Serfs*24) 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).
GeneDx	RCV002293415	SCV002586839	pathogenic	not provided	2022-03-30	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, while also shown to result in aberrant splicing resulting in multiple transcripts including deletion exon 5 (Sanz 2010, Stauffer 2020); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Li 2008, Cao 2016, Weren 2016, Sun 2017); Published functional studies demonstrate a damaging effect: reduced cell viability and hypersensitivity to DNA damaging agents (Stauffer 2020); 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 698_702del or 469_473del; This variant is associated with the following publications: (PMID: 30720863, 28176296, 30702160, 31174498, 27060066, 29487695, 28294317, 26295337, 33563323, 32926049, 26852015, 32623769, 30883759, 31825140, 17851763, 20215541, 22632462, 32393813, 28724667, 27767231)
Fulgent Genetics, Fulgent Genetics	RCV005007969	SCV005634393	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-02-29	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077336	SCV000109133	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2006-12-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077336	SCV000146926	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496831	SCV000587551	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research