ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8023A>G (p.Ile2675Val) (rs397507954)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000258421 SCV001161555 pathogenic Breast-ovarian cancer, familial 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 = 0.999651
Invitae RCV000045390 SCV000073403 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2675 of the BRCA2 protein (p.Ile2675Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in many individuals and families affected with breast and/or ovarian cancer (PMID: 18424508, 23683081, 24249303, 25802882, 26757417, 27157322, 27741520). ClinVar contains an entry for this variant (Variation ID: 52475). Experimental RT-PCR and mini-gene splicing assays have shown that this sequence change creates a strong donor splice site, resulting in the removal of 309 nucleotides (r.8023_8331del) of exon 18 and the in-frame deletion of 103 amino acid residues (p.Ile2675_Lys2777del) (PMID: 18424508, 22505045, 27157322, 28339459) At least three different missense substitutions within the deleted region of BRCA2 (p.Thr2722Arg, p.Asp2723Gly, p.Asp2723His) are reported to be deleterious (PMID: 12145750, 21990134, 15290653, 16489001). This indicates that the residues included in the deleted region are important for BRCA2 protein function. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000132001 SCV000187060 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-13 criteria provided, single submitter clinical testing The p.I2675V variant (also known as c.8023A>G), located in coding exon 17 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8023. The isoleucine at codon 2675 is replaced by valine, an amino acid with highly similar properties. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site. Two independent studies using RT-PCR and a splicing mini-gene assays indicate that this new donor site results in an abnormal transcript with the inclusion of only 46 nucleotides of the exon and the in-frame loss of 309 nucleotides (Bonnet C et al. J Med Genet. 2008 Jul;45(7):438-46; Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13:e1006691). In addition, this alteration has been reported in multiple individuals with personal and/or family history consistent with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Blay P et al. BMC Cancer. 2013 May;13:243; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Hirotsu Y et al. Mol Genet Genomic Med. 2015 Mar;3:121-9; Hirotsu Y et al. Oncotarget. 2017 Dec;8:114463-114473; Wen WX et al. J. Med. Genet. 2018 02;55:97-103; Liu Y et al. Mol Genet Genomic Med. 2019 03;7:e493; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 RCV000258421 SCV000327800 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000258421 SCV000785232 pathogenic Breast-ovarian cancer, familial 2 2017-06-20 criteria provided, single submitter clinical testing
GeneKor MSA RCV000045390 SCV000821715 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-01-01 criteria provided, single submitter clinical testing This variant is a missense mutation replaces Isoleucine with Valine at codon 2675 of the BRCA2 protein. The isoleucine residue is highly conserved in a functional domain of the protein and there is a small physiochemical difference between isoleucine and valine (Grantham Score 29). This sequence change is not present in population databases (rs397507954, no ExAC). It has been described in literature in individuals and families affected with breast and/or ovarian cancer (PMID: 18424508, PMID: 25802882, PMID: 26757417, PMID: 27741520, PMID: 27157322 ). ClinVar contains multiple entries for this variant (Variation ID: 52475). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be detrimental to protein function, a prediction which is supported by experimental RT-PCR and mini-gene splicing assays which show that this missense change creates a strong donor splice site, resulting in the removal of 309 nucleotides (r.8023_8331del) of exon 18 and the in-frame deletion of 103 amino acid residues (p.Ile2675_Lys2777del) (PMID: 22505045, PMID: 18424508 , PMID: 28339459 ). At least three different missense substitutions within the deleted region of BRCA2 (p.Thr2722Arg, p.Asp2723Gly, p.Asp2723His) are reported to be deleterious (PMID: 12145750 , PMID: 21990134 , PMID: 15290653, PMID: 16489001). This indicates that the residues included in the deleted region are important for BRCA2 protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045390 SCV001362935 pathogenic Hereditary breast and ovarian cancer syndrome 2020-11-19 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8023A>G (p.Ile2675Val) results in a conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict that the variant creates a cryptic exonic 5-prime donor site. These predictions were confirmed by experimental evidence which demonstrated that the variant results in loss of a stretch of 309 nucleotides at the 3-prime terminal of exon 18 from the mRNA. Multiple studies observed abundant aberrant product and a complete absence of wild type product (Fraile-Bethencourt_2017, Houdayer_2012, Bonnet_2008). The variant allele was found at a frequency of 4e-06 in 251076 control chromosomes. c.8023A>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rebbeck_2018, Hirotsu_2015, Blay_2013, Bonnet_2008, Palma_2008). These data indicate that the variant is very likely to be associated with disease. Six other ClinVar submitters (evaluation after 2014), including two expert panels, have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.