Submissions for variant NM_000059.4(BRCA2):c.994del (p.Ile332fs)

dbSNP: rs80359777

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)	RCV000112872	SCV000300378	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254766	SCV000296739	pathogenic	not provided	2019-09-30	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.
GeneKor MSA	RCV000045923	SCV000296841	pathogenic	Familial cancer of breast	2016-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000254766	SCV000321449	pathogenic	not provided	2021-10-26	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 a personal or family history consistent with pathogenic variants in this gene (Turner 1999, Fackenthal 2012, Kim 2012, Kang 2015, Rebbeck 2018); Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1222delA; This variant is associated with the following publications: (PMID: 10506595, 24156927, 28205045, 28392550, 29446198, 29673794, 31825140, 31002019, 26187060, 24549055, 31026599, 22034289, 22798144, 25863477)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112872	SCV000328178	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574932	SCV000661202	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-08	criteria provided, single submitter	clinical testing	The c.994delA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 994, causing a translational frameshift with a predicted alternate stop codon (p.I332Ffs*17). This alteration has been detected in multiple families with breast and/or ovarian cancer (Turner BC et al, J. Clin. Oncol. 1999 Oct; 17(10):3017-24; Kim H et al. Breast Cancer Res. Treat., 2012 Aug;134:1315-26; Park B et al. Breast Cancer Res. Treat., 2017 May;163:139-150; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Of note, this alteration is also designated as 1222delA 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.
Color Diagnostics, LLC DBA Color Health	RCV000574932	SCV000684103	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496857	SCV001587688	pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52924). This variant is also known as 1222delA. This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 10506595, 22798144, 24549055, 28205045). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile332Phefs*17) 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).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000254766	SCV002010282	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000254766	SCV004242771	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112872	SCV000145802	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1998-04-02	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496857	SCV000587577	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353657	SCV000591724	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ile332PhefsX17 variant was not identified in the literature. The variant was identified in dbSNP (ID: rs80359778) “With Pathogenic allele”, LOVD, the ClinVar database (classified as a pathogenic variant by BIC), the BIC database (3X with clinical importance), and UMD (1X as a causal variant). The p.Ile332PhefsX17 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 332 and leads to a premature stop codon 17 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.