Submissions for variant NM_000059.4(BRCA2):c.6393del (p.Lys2131fs)

dbSNP: rs886038145

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)	RCV000240998	SCV000301029	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	RCV000240998	SCV000327411	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496262	SCV000918885	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-09-04	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6393delA (p.Lys2131AsnfsX6) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Tyr3098X, p.Arg3128X, p.Tyr3308X, etc.). This variant is absent in 118276 control chromosomes from ExAC. In addition, multiple clinical diagnostic laboratories/reputable databases in ClinVar have classified this variant as pathogenic. To our knowledge, the variant has not been reported in affected individuals in literature, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Ambry Genetics	RCV001025212	SCV001187357	pathogenic	Hereditary cancer-predisposing syndrome	2019-05-03	criteria provided, single submitter	clinical testing	The c.6393delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 6393, causing a translational frameshift with a predicted alternate stop codon (p.K2131Nfs*6). 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 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496262	SCV001237285	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-13	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: 254580). This premature translational stop signal has been observed in individual(s) with increased risk of breast and/or ovarian cancer (PMID: 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys2131Asnfs*6) 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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800619	SCV002046386	pathogenic	not provided	2020-11-11	criteria provided, single submitter	clinical testing	This frameshift variant is predicted to cause the premature termination of BRCA2 protein synthesis. It has been reported in at least one family with increased risk of breast and/or ovarian cancer in the published literature (PMID: 29446198 (2018)). This variant has not been reported in large, multi-ethnic general populations. Internal laboratory data indicates that this variant was detected in an individual with a phenotype consistent with disease. Therefore, this variant is classified as pathogenic.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496262	SCV000587841	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004725128	SCV005335428	likely pathogenic	BRCA2-related disorder	2024-04-26	no assertion criteria provided	clinical testing	The BRCA2 c.6393delA variant is predicted to result in a frameshift and premature protein termination (p.Lys2131Asnfs*6). This variant has been reported in an individual with increased risk of breast and/or ovarian cancer (Rebbeck et al. 2018. PMID: 29446198, Supplementary Table 1). This variant has not been reported in a large population database, indicating this variant is rare. This variant has interpretations ranging from likely pathogenic to pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/254580/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as likely pathogenic.