Submissions for variant NM_000059.4(BRCA2):c.4554del (p.Glu1518fs)

dbSNP: rs80359458

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113319	SCV000300765	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	RCV000113319	SCV000327053	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000113319	SCV000677679	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-11-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000581479	SCV000688881	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496545	SCV000694779	pathogenic	Hereditary breast ovarian cancer syndrome	2016-03-09	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.4554delA variant results in a premature termination codon at codon 1542, predicted to cause a truncated or absent BRCA2 protein due to non-sense mediated decay, which are commonly known mechanisms for HBOC. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Tyr3308X, p.Ser3147fs). Mutation Taster predicts a damaging outcome for this variant. This variant was not found in 120318 control chromosomes, but was identified in multiple breast cancer patients in the literature. In addition, several clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Ambry Genetics	RCV000581479	SCV001184455	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-28	criteria provided, single submitter	clinical testing	The c.4554delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 4554, causing a translational frameshift with a predicted alternate stop codon (p.E1518Dfs*25). This alteration was detected in 1/989 unrelated individuals from a cohort of German breast/ovarian cancer families (Meindl A et al. Int. J. Cancer, 2002 Feb;97:472-80). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001091963	SCV001248274	pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496545	SCV001580395	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1518Aspfs*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 4782delA, 4781delA. ClinVar contains an entry for this variant (Variation ID: 51671). For these reasons, this variant has been classified as Pathogenic.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000496545	SCV002504851	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473344	SCV004212885	pathogenic	Familial cancer of breast	2021-11-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001091963	SCV004219640	pathogenic	not provided	2022-12-07	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. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 11802209 (2002)). Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000113319	SCV004845693	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-31	criteria provided, single submitter	clinical testing	The c.4554del (p.Glu1518Aspfs*25) variant in the BRCA2 gene is located on the exon 11 and is predicted to result in shift of reading frame that introduces a premature translation termination codon (p.Glu1518Aspfs*25), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 29446198, 11897832, 8988179). The variant has been reported in 3 unrelated individuals with ovarian cancer, hepatocellular carcinoma, or pancreatic ductal adenocarcinoma (PMID: 29483665, 34250406, 29483665). The variant is reported in ClinVar as pathogenic (ID: 51671) and reviewed by the expert panel. This variant is absent in the general population database (gnomAD). Therefore, the c.4554del (p.Glu1518Aspfs*25) variant of BRCA2 has been classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113319	SCV000146446	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113319	SCV000297527	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-05-27	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496545	SCV000587716	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research