Submissions for variant NM_000059.4(BRCA2):c.4965del (p.Cys1654_Tyr1655insTer)

dbSNP: rs80359475

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077343	SCV000300810	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044534	SCV000072547	pathogenic	Hereditary breast ovarian cancer syndrome	2023-02-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1655*) 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 and ovarian cancer (PMID: 21709188, 27836010, 28724667, 29487695). ClinVar contains an entry for this variant (Variation ID: 51751). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077343	SCV000327116	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018932	SCV005027564	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-12	criteria provided, single submitter	clinical testing	The c.4965delC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 4965, causing a translational frameshift with a predicted alternate stop codon (p.Y1655*). This alteration was identified in an individual diagnosed with pancreatic cancer (Yin L et al. JAMA Netw Open, 2022 Feb;5:e2148721). This variant was also identified in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Norquist B et al. J Clin Oncol, 2011 Aug;29:3008-15; Shao D et al. Cancer Sci, 2020 Feb;111:647-657). Of note, this alteration is also known as 5193delC 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.
Sharing Clinical Reports Project (SCRP)	RCV000077343	SCV000109140	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-01-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077343	SCV000146516	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	RCV000044534	SCV000587736	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research