Submissions for variant NM_000059.4(BRCA2):c.8817_8820del (p.Lys2939fs)

dbSNP: rs397508010

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000257676	SCV000324696	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-18	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	RCV000257676	SCV000327972	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001185074	SCV001351221	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-20	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 22 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 two African individuals affected with breast cancer (PMID: 22034289, 22739995). 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.
Genetic Services Laboratory, University of Chicago	RCV001818222	SCV002065849	pathogenic	not provided	2022-01-09	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA2 gene demonstrated a four base pair deletion in exon 22, c.8817_8820del. This sequence change results in an amino acid frameshift and creates a premature stop codon 36 amino acids downstream of the sequence change, p.Lys2939Asnfs*36. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA2 protein with potentially abnormal function. This sequence change has previously been described in individuals with breast cancer (PMID: 22034289, 22739995). This sequence change has not been described in the gnomAD population database (rs397508010). Collectively these evidences suggest that, the c.3028del change is pathogenic.
Ambry Genetics	RCV001185074	SCV002683850	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-31	criteria provided, single submitter	clinical testing	The c.8817_8820delGAAA pathogenic mutation, located in coding exon 21 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 8817 to 8820, causing a translational frameshift with a predicted alternate stop codon (p.K2939Nfs*36). This alteration was identified in two Yoruban patients from a Nigerian breast cancer cohort (Fackenthal JD et al. Int J Cancer, 2012 Sep;131:1114-23; 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	RCV001818222	SCV004220628	pathogenic	not provided	2023-02-11	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. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 22034289 (2012) and 22739995 (2012)). Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003529948	SCV004297193	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys2939Asnfs*36) 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 premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 22034289). This variant is also known as 9045delGAAA. ClinVar contains an entry for this variant (Variation ID: 52684). For these reasons, this variant has been classified as Pathogenic.
GenomeConnect, ClinGen	RCV002508919	SCV002818335	not provided	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; Melanoma, cutaneous malignant, susceptibility to, 1		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 01-10-2022 by Lab or GTR ID 1238. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.