Submissions for variant NM_000059.4(BRCA2):c.2834_2835del (p.Lys945fs)

dbSNP: rs80359356

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113099	SCV000300565	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	RCV000113099	SCV000326773	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177893	SCV001342194	pathogenic	Hereditary cancer-predisposing syndrome	2019-07-18	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides 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. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. 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. Based on available evidence, this variant is classified as Pathogenic.
Division of Medical Genetics, University of Washington	RCV000113099	SCV001424784	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-02-13	criteria provided, single submitter	clinical testing	The c.2834_2835delAA variant results in a translational frameshift and the introduction of a premature termination codon 13 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of BRCA2 is a well-established mechanism of disease for HBOC. Thus, this variant is interpreted as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496919	SCV001589000	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-17	criteria provided, single submitter	clinical testing	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: 29446198). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55791). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys945Argfs*13) 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).
Ambry Genetics	RCV001177893	SCV002748432	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-27	criteria provided, single submitter	clinical testing	The c.2834_2835delAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 2834 to 2835, causing a translational frameshift with a predicted alternate stop codon (p.K945Rfs*13). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496919	SCV003928239	pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2834_2835delAA (p.Lys945ArgfsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250426 control chromosomes (gnomAD). c.2834_2835delAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer (Rebbeck_2018). The following publication has been ascertained in the context of this evaluation (PMID: 29446198). Six submitters (including an expert panel, ENIGMA) have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496919	SCV004847875	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Lys945ArgfsX13 variant in BRCA2 has not been previously reported in individuals with hereditary breast and/or ovarian cancer (HBOC) and was absent from large population studies, but has been reported in ClinVar (Variation ID: 55791). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 945 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113099	SCV000146124	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113099	SCV000297516	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-06-22	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496919	SCV000587646	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353966	SCV000591828	pathogenic	not provided		no assertion criteria provided	clinical testing