Submissions for variant NM_000059.4(BRCA2):c.9682del (p.Ser3228fs)

dbSNP: rs398122618

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)	RCV000077047	SCV000301410	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	RCV000077047	SCV000328163	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580915	SCV000684084	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the RAD51 binding domain. This domain has been reported to be essential for homologous recombination and DNA repair (PMID: 17515903), therefore this variant is expected to result in an absent or non-functional protein product. In addition, truncating variants occurring downstream of this variant are classified as pathogenic (ClinVar Variation ID: 1069551, 823404, 548323). This variant has been reported in individuals affected with high-risk breast cancer (PMID: 26183948, 35261632; Color internal data). This variant has been identified in 1/249942 chromosomes 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.
GeneKor MSA	RCV000580915	SCV000693594	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-09	criteria provided, single submitter	clinical testing	This variant is a deletion of 1 nucleotide from exon 27 of the BRCA2 mRNA (c.9682delA), causing a frameshift at codon 3228. This creates a premature translation stop signal 21 amino acid residues later and is expected to result in an absent or disrupted protein product. The mutation database ClinVar contains an entry for this variant (Variation ID: 91530)
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269611	SCV001449711	pathogenic	not provided	2018-02-23	criteria provided, single submitter	clinical testing
Invitae	RCV001854350	SCV002246510	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 17026620, 18593900, 18607349, 22711857). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 91530). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26183948). This variant is present in population databases (rs398122618, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ser3228Valfs*21) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 191 amino acid(s) of the BRCA2 protein.
GeneDx	RCV001269611	SCV002601191	pathogenic	not provided	2022-11-03	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in the published literature (Dodova et al., 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9910delA; This variant is associated with the following publications: (PMID: 29310832, 26183948, 30720243, 31159747, 29922827)
Ambry Genetics	RCV000580915	SCV002692136	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-05	criteria provided, single submitter	clinical testing	The c.9682delA pathogenic mutation, located in coding exon 26 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 9682, causing a translational frameshift with a predicted alternate stop codon (p.S3228Vfs*21). This mutation was observed in a Bulgarian woman with bilateral breast cancer diagnosed at age 52 (Dodova RI et al. BMC Cancer 2015 Jul;15:523). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Sharing Clinical Reports Project (SCRP)	RCV000077047	SCV000108844	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-10-18	no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554257	SCV001774866	pathogenic	Breast carcinoma	2021-08-08	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077047	SCV004243878	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing