Submissions for variant NM_000059.4(BRCA2):c.5585_5588del (p.Val1862fs)

dbSNP: rs80359523

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077354	SCV000300899	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.
Ambry Genetics	RCV000162925	SCV000213412	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	clinical testing	The c.5585_5588delTGAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5585 to 5588, causing a translational frameshift with a predicted alternate stop codon (p.V1862Efs*11). This mutation was reported in one woman with a personal history of breast cancer diagnosed after age 50 (Tung N et al. Cancer 2015 Jan;121:25-33) and was also identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). 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.
GeneDx	RCV000223488	SCV000278861	pathogenic	not provided	2024-05-07	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; Observed in individuals with BRCA2-related cancers (PMID: 27433846, 25186627); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5813_5816delTGAA or 5813del4; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 27433846, 25186627, 29446198, 31853058)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077354	SCV000327237	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	RCV000223488	SCV000885098	pathogenic	not provided	2018-03-13	criteria provided, single submitter	clinical testing	The BRCA2 c.5585_5588del; p.Val1862fs variant (rs80359523) has been described in individuals affected with breast and prostate cancer (Pritchard 2016, Tung 2015). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 51885) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Pritchard C et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496517	SCV000916831	pathogenic	Hereditary breast ovarian cancer syndrome	2020-11-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5585_5588delTGAA (p.Val1862GlufsX11) 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. The variant was absent in 245466 control chromosomes (gnomAD). c.5585_5588delTGAA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (example: Tung_2014, Rebbeck_2018) and also in an individual with prostate cancer (Pritchard_2016). In addition, BIC database reports 5 individuals with this variant (NHGRI BIC). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters (evaluation after 2014), including an expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000223488	SCV001470432	pathogenic	not provided	2020-06-19	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 25186627 (2015)) and prostate cancer (PMID: 27433846 (2016)). Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496517	SCV001589624	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val1862Glufs*11) 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 prostate cancer and breast cancer (PMID: 25186627, 27433846). ClinVar contains an entry for this variant (Variation ID: 51885). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003473361	SCV004212848	pathogenic	Familial cancer of breast	2022-02-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000223488	SCV004238739	pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077354	SCV000109151	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-09-09	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077354	SCV000146638	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496517	SCV000587776	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research