ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9256_9256+1delinsTA (rs587781422)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129299 SCV000184060 pathogenic Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing ​The c.9256_9256+1delGGinsTA pathogenic mutation (also known as p.G3086*), results from a GG to TA substitution spanning the last nucleotide of coding exon 23 to the first nucleotide after coding exon 23 of the BRCA2 gene. This changes the amino acid from a glycine to a stop codon at position 3086, which spans coding exons 23 and 24. In one study, the c.9256+1G>A alteration (also designated as IVS24+1G>A) was shown to produce aberrant transcripts with exon 23 skipping and premature truncation in lympocytes at the mRNA level and was detected in two individuals from a family with at least two first degree relatives with breast and/or ovarian cancer at a young ages (Claes K et al. Genes Chromosomes Cancer. 2003 Jul;37:314-20). In addition, in a separate functional study using minigene assays, the c.9256+1G>A alteration resulted in aberrant splicing, including skipping of coding exon 23 (Acedo A et al. Breast Cancer Res. 2012 May;14:R87). 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.
Invitae RCV000546503 SCV000635728 pathogenic Hereditary breast and ovarian cancer syndrome 2019-05-31 criteria provided, single submitter clinical testing This sequence change affects the last nucleotide of exon 24 and a donor splice site in intron 24 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 disease. ClinVar contains an entry for this variant (Variation ID: 140992). This variant recapitulates two adjacent variants (c.9256G>T and c.9256+1G>A) on the same chromosome, which have been reported in a family with breast and/or ovarian cancer, and were shown to disrupt RNA splicing, and determined to be pathogenic (PMID: 12759930, 22632462). This suggests that these nucleotides are important for normal RNA splicing and protein function. 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). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000592883 SCV000709686 pathogenic not provided 2015-06-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9256_9256+1delGGinsTA and consists of a deletion and insertion of two nucleotides at the last nucleotide of exon 24 and the +1 position of intron 24. Using alternate nomenclature, this variant would be defined as BRCA2 9484_9484+1delGGinsTA. The normal sequence, with the bases that are deleted in braces and inserted in brackets, is AACA[Gg][Ta]taat, where the capital letters are exonic and lowercase are intronic. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the currently available information, we consider BRCA2 c.9256_9256+1delGGinsTA to be a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000546503 SCV000918904 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-09-07 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9256_9256+1delinsTA variant involves the alteration of a conserved dinucleotide sequence (GG>TA) leading to the alteration of the canonical splice site at the boundary of exon 24 and intron 24. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing. ESE finder predicts that this variant may also affect the binding site of splicing factors (SF2/ASF, SRp40). The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Nevertheless, single nucleotide substitution variants affecting the same dinucleotide sequence positions and leading to the same base substitutions (i.e. c.9256G>T and c.9256+1G>A) have been reported in the literature, and c.9256+1G>A was shown in in vitro studies (Acedo 2015) leading to protein truncation (through splice site destruction and exon skipping). Moreover, both variants were classified as pathogenic by clinical diagnostic laboratories/reputable databases. Based on these data, the variant of interest is expected to affect a canonical splice site or lead to a nonsense alteration, both causing protein truncation. In addition, at least one clinical diagnostic laboratory (Ambry Genetics) classified the variant of interest as pathogenic, though they provided no further evidence for independent evaluation. Taken together, this variant is classified as likely pathogenic.

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