Submissions for variant NM_000059.4(BRCA2):c.8633-24_8634del

dbSNP: rs886040945

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000258374	SCV001161649	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.990758
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258374	SCV000327937	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774948	SCV000909034	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	clinical testing	This variant causes a 26 nucleotide deletion from the -24 position in intron 20 into exon 21 of the BRCA2 gene. RNA studies have shown that this variant causes exon 21 skipping, resulting in a frameshift and premature translation stop signal (PMID: 25382762). This variant has not 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036379	SCV001199740	pathogenic	Hereditary breast ovarian cancer syndrome	2020-08-07	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). This variant has been observed in a family affected with hereditary breast and/or ovarian cancer (PMID: 29446198). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). This variant is also known as c.8633-24_8634del in the literature. ClinVar contains an entry for this variant (Variation ID: 267703). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 20 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics	RCV000774948	SCV004096091	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-11	criteria provided, single submitter	clinical testing	The c.8633-24_8634del26 variant results from a deletion of 26 nucleotides starting 24 nucleotides before coding exon 20 and including the first 2 nucleotides of coding exon 20 of the BRCA2 gene. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). This alteration was also classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat. 2019 Sep;40(9):1557-1578). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This deletion includes the canonical acceptor site of coding exon 20, which is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV003475883	SCV004211848	pathogenic	Familial cancer of breast	2023-10-17	criteria provided, single submitter	clinical testing