ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7007G>T (p.Arg2336Leu) (rs28897743)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045114 SCV000073127 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 2336 of the BRCA2 protein (p.Arg2336Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant also falls at the last nucleotide of exon 13 of the BRCA2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 22970155, 27157322, 29446198). ClinVar contains an entry for this variant (Variation ID: 52242). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. A different variant affecting this nucleotide (c.7007) has been determined to be pathogenic (PMID: 25447315, 21719596, 9150172). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.
Ambry Genetics RCV000219635 SCV000277916 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-29 criteria provided, single submitter clinical testing The c.7007G>T variant (also known as p.R2336L), located in coding exon 12 of the BRCA2 gene, results from a G to T substitution at nucleotide position 7007. The amino acid change results in arginine to leucine at codon 2336, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in individuals with herediatry breast and/or ovarian cancer, predominantly from Chinese cohorts (Kwong A et al. PLoS ONE. 2012;7(9):e43994; Wei H et al. Oncol Lett 2018 Jun;15(6):9420-9428; Bhaskaran S et al. Int. J. Cancer 2019 Jan). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113685 SCV000327567 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000219635 SCV000683839 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759653 SCV000889121 likely pathogenic not provided 2018-01-12 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000113685 SCV001434898 likely pathogenic Breast-ovarian cancer, familial 2 2018-10-05 criteria provided, single submitter clinical testing This c.7007G>T (p.Arg2336Leu) variant in exon 13 of the BRCA2 gene is the last base of exon 13 and is predicted to alter splicing resulting in a frame shift. This variant has been reported in patients with breast cancer (PMID: 22970155) and is not observed in general population databases. Other nucleotide base substitutions at this same site have also been observed to alter splicing and are considered pathogenic (PMID: 18489799, 9150172). Therefore, the c.7007G>T (p.Arg2336Leu) variant in the BRCA2 gene is classified as likely pathogenic.
Research and Development, ARUP Laboratories RCV001646607 SCV001854356 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA2) RCV000113685 SCV000146993 pathogenic Breast-ovarian cancer, familial 2 2013-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045114 SCV000587877 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000759653 SCV001550372 likely pathogenic not provided no assertion criteria provided clinical testing The BRCA2 p.Arg2336Leu variant was identified in 4 of 2798 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Kwong 2012, Kwong 2016). The variant was also identified in dbSNP (ID: rs28897743) as “With Pathogenic allele ", in ClinVar (classified as likely pathogenic by Invitae, Ambry Genetics, Color Genomics; as pathogenic by CIMBA, COGR, BIC), MutDB, LOVD 3.0 (1x as pathogenic), BIC Database (2x with clinical importance), and in ARUP Laboratories (as Definitely pathogenic). The variant was not identified in GeneInsight-COGR, Cosmic, UMD-LSDB, and Zhejiang University Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In UMD, 2 alternate substitutions at this same nucleotide position (c.7007G>A, p.Arg2336His and c.7007G>C, p.Arg2336Pro) have been classified as causal, with evidence showing the G>A substitution causes a 70 bp deletion in exon 13 resulting in a frameshift that introduces a premature stop codon 30 codons into exon 14. Lymphocyte RT-PCR analysis showed the alternate variant c.7007G>A caused exon 13 skipping, in agreement with bionformatic studies which conclude a weakening and disruption of the splice site (Sanz 2010). A bioinformatic tool applying information theory to analyze splicing variants found the natural donor site was weakened for an alternate substitution variant (c.7007G>A), concordant with other splicing models/testing (Mucaki 2010). The p.Arg2336 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Arg2336Leu variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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