Submissions for variant NM_000059.4(BRCA2):c.1499del (p.Gly500fs)

dbSNP: rs397507591

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077258	SCV000300434	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	RCV000077258	SCV000326561	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496652	SCV000605809	pathogenic	Hereditary breast ovarian cancer syndrome	2016-12-23	criteria provided, single submitter	clinical testing	The p.Gly500fs variant in BRCA2 has been reported in at least 2 individuals with BRCA2-associated cancers (Meindl 2002) and was absent from large population stu dies. The p.Gly500fs variant is predicted to cause a frameshift, which alters t he protein?s amino acid sequence beginning at position 500 and leads to a premat ure termination codon 9 amino acids downstream. This alteration is then predicte d to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on Septem ber 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300434.2) . In summary, this variant meets criteria to be classified as pathogenic for HBO C in an autosomal dominant manner based upon segregation studies and the predict ed impact to the protein.
Ambry Genetics	RCV000565720	SCV000668865	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-03	criteria provided, single submitter	clinical testing	The c.1499delG pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1499, causing a translational frameshift with a predicted alternate stop codon (p.G500Vfs*9). This alteration, designated 1727delG, was detected in 2/989 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496652	SCV000959498	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 51135). This variant is also known as 1727delG. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 11802209). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly500Valfs*9) 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).
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269907	SCV001450262	pathogenic	not provided	2014-12-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001269907	SCV001470196	pathogenic	not provided	2019-12-13	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001269907	SCV001905529	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001269907	SCV002820717	pathogenic	not provided	2022-07-07	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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Meindl 2002); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1727delG; This variant is associated with the following publications: (PMID: 20104584, 11802209, 31825140, JiangY2021[preprint], 19941162, 30702160)
CeGaT Center for Human Genetics Tuebingen	RCV001269907	SCV002822064	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2
Sharing Clinical Reports Project (SCRP)	RCV000077258	SCV000109055	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2009-02-03	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496652	SCV000587599	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785214	SCV000923782	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000077258	SCV004244220	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing