ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.68-1G>T (rs1060502376)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000458301 SCV000549480 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-01-18 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 409412). 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. 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000483572 SCV000569905 uncertain significance not provided 2016-04-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.68-1G>T or IVS2-1G>T and consists of a G>T nucleotide substitution at the -1 position of intron 2 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 296-1G>T. This particular variant has not, to our knowledge, been published in the literature. Although this variant destroys a canonical splice acceptor site and is predicted to cause abnormal splicing of exon 3, the skipping of exon 3 is predicted to be an in-frame event. Since the rest of the protein is expected to be translated, the loss of this one exon with no crucial functional domains has unclear clinical significance. Furthermore, a naturally occurring transcript of BRCA2 that lacks exon 3 has been reported in normal tissues and controls (Diez 2007, Muller 2011). In the absence of RNA or functional studies, the actual effect of this variant is unknown. We consider BRCA2 c.68-1G>T to be a variant of uncertain significance.
Color Health, Inc RCV000775799 SCV000910252 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000775799 SCV001187931 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing The c.68-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 2 of the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to abolish the native splice acceptor site, but is predicted to weaken (but not abolish) the efficiency of the native splice acceptor site by BDGP; however, direct evidence is unavailable. 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354033 SCV000591658 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The c.68-1G>T variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), LOVD, COSMIC, ClinVar, GeneInsight COGR, BIC or UMD. The c.68-1G>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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