Submissions for variant NM_000059.4(BRCA2):c.8023A>G (p.Ile2675Val)

dbSNP: rs397507954

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV000258421	SCV004101416	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-04-23	reviewed by expert panel	curation	The c.8023A>G variant in BRCA2 is a missense variant predicted to cause substitution of Isoleucine by Valine at amino acid 2675 (p.Ile2675Val). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and mini-gene assays demonstrated that the variant impacts splicing by creation of a donor site, resulting in skipping of 309nt of exon 18 (PMIDs: 18424508, 22505045, 28339459). All studies report no wild-type transcript from the variant allele. Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1612 (based on Cosegregation LR=605.1; Pathology LR=0.88; Co-occurrence LR=1.05; Family History LR=2.88), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_Very strong).
Invitae	RCV000045390	SCV000073403	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2675 of the BRCA2 protein (p.Ile2675Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 103 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs397507954, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 18424508, 23683081, 24249303, 25802882, 26757417, 27157322, 27741520). ClinVar contains an entry for this variant (Variation ID: 52475). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 18 (PMID: 18424508, 22505045, 27157322, 28339459, 31191615; Invitae). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Asp2723His) have been determined to be pathogenic (PMID: 15290653, 15695382, 16489001, 18607349, 23108138, 25146914). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000132001	SCV000187060	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-12	criteria provided, single submitter	clinical testing	The c.8023A>G variant (also known as p.I2675V), 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. RNA studies have shown that this alteration creates a new donor site that results in an abnormal transcript with an in-frame loss of 309 nucleotides (Ambry internal data; 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 nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. 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, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000258421	SCV000785232	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-20	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000045390	SCV000821715	likely pathogenic	Hereditary breast 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 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.
GeneDx	RCV001550183	SCV001770473	likely pathogenic	not provided	2021-07-12	criteria provided, single submitter	clinical testing	Exonic splice variant demonstrated to result in aberrant splicing, resulting in the in-frame deletion of 309 nucleotides (Bonnet 2014, Fraile-Bethencourt 2017); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (Lek 2016); Observed in multiple individuals with a personal and/or family history consistent with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Blay 2013, Hirotsu 2015, Nakamura 2015, Fernandes 2016, Ng 2016, Sakamoto 2016); Multifactorial likelihood analysis suggests this variant is pathogenic (Parsons 2019); Also known as 8251A>G; This variant is associated with the following publications: (PMID: 32377563, 31159747, 30720243, 30652428, 29176636, 31214711, 30287823, 28993434, 30415210, 29446198, 28111427, 12228710, 27535533, 29907814, 32862574, 33875706, 23683081, 25802882, 24249303, 27741520, 26757417, 26439132, 31131967, 28339459, 18424508, 22505045, 27157322)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001550183	SCV002047327	pathogenic	not provided	2021-02-11	criteria provided, single submitter	clinical testing	This variant has been reported in healthy controls and in individuals affected with breast or ovarian cancer in the published literature (PMID: 30652428 (2019), 30287823 (2018), 29907814 (2018), 29383094 (2017), 28993434 (2018)). Additionally, functional studies indicate that this variant interferes with normal BRCA2 mRNA splicing (PMID: 28339459 (2017), 22505045 (2012), 18424508 (2008)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. Variant is located in potentially critical domain of the protein. Therefore, the variant is classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV002272041	SCV002556519	pathogenic	Familial cancer of breast	2020-10-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483046	SCV002775486	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-05-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001550183	SCV003812564	pathogenic	not provided	2022-02-22	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000258421	SCV003932761	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002272041	SCV004213683	pathogenic	Familial cancer of breast	2023-08-09	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002272041	SCV004239120	pathogenic	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and nonpolar, with valine, which is neutral and non-polar, at codon 2675 of the BRCA2 protein (p.Ile2675Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 103 amino acid residue(s), This nucleotide position is highly conserved. This variant is present in population databases (rs397507954, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 18424508, 23683081, 24249303, 25802882, 26757417, 27157322, 27741520). ClinVar contains an entry for this variant (Variation ID: 52475). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Asp2723His) have been determined to be pathogenic (PMID: 15290653, 15695382, 16489001, 18607349, 23108138, 25146914). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
BRCAlab, Lund University	RCV000258421	SCV002588918	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162386	SCV002758368	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research