Submissions for variant NM_000059.4(BRCA2):c.6566dup (p.Asn2189fs)

dbSNP: rs397507373

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031635	SCV000301067	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.
Invitae	RCV000122925	SCV000166183	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn2189Lysfs*8) 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. ClinVar contains an entry for this variant (Variation ID: 38053). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000160303	SCV000210784	pathogenic	not provided	2023-10-30	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 in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6794dupA; This variant is associated with the following publications: (PMID: 30263092, 30787465, 30322717, 28888541)
Ambry Genetics	RCV000214634	SCV000273753	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-22	criteria provided, single submitter	clinical testing	The c.6566dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 6566, causing a translational frameshift with a predicted alternate stop codon (p.N2189Kfs*8). This mutation was identified in a cohort of 4439 women with ovarian cancer undergoing multigene panel testing at one laboratory (Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488). This mutation was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160303	SCV000296613	pathogenic	not provided	2020-08-07	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in an individual affected with ovarian cancer (BRCA Exchange (http://brcaexchange.org/), PMID: 30322717 (2018)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031635	SCV000327463	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214634	SCV000905020	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	This variant inserts 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 been reported in at least 1 individual affected with ovarian cancer (PMID: 30322717). 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.
Fulgent Genetics, Fulgent Genetics	RCV002482933	SCV002775753	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-10-14	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031635	SCV003932748	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	A pathogenic variant was detected in this sample in BRCA2 gene . This sequence change creates a premature translational stop signal (p.Asn2189Lysfs*8) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Lossof- function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (GenomAD). This variant is associated with the following publications: (PMID: 30263092, 30322717). ClinVar contains an entry for this variant (Variation ID: 38053) submitted by eight clinical labs after 2014 and all classify this variant as pathogenic . For these reasons, this variant has been classified as Pathogenic. This variant confirmed by Sanger Sequencing .
Baylor Genetics	RCV003473204	SCV004210372	pathogenic	Familial cancer of breast	2023-03-21	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031635	SCV000054242	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-02-29	no assertion criteria provided	clinical testing