ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4096+1G>A (rs80358178)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031146 SCV000783125 uncertain significance Breast-ovarian cancer, familial 1 2018-04-12 reviewed by expert panel curation Clinical data collected by the ENIGMA consortium demonstrates that the BRCA1 c.4096+1G>A variant may not exhibit the clinical characteristics of a standard high-risk pathogenic BRCA1 variant (Spurdle, unpublished data). This splice site variant has been proven to result in production of naturally occurring in-frame transcripts delta11q (Bonatti et al., 2006 - PMID: 17011978) and delta11 (Radice, unpublished data). Since no clinically relevant domain has been described in BRCA1 exon 11 (ENIGMA rules), the splicing alteration is compatible with the clinical data, and supports Class-3 classification.
Invitae RCV000195364 SCV000076454 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs80358178, ExAC 0.004%). This variant has been reported in individuals affected with ovarian (PMID: 17011978) and breast cancer (PMID: 27328445, 21156238, 29116469). This variant has been observed in an individual also carrying a different BRCA1 pathogenic allele (Invitae), which suggests that this c.4096+1G>A variant may not be the primary cause of disease. This variant is also known as IVS11+1G>A and c.4215+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37565). Experimental studies have shown that this sequence change alters splicing of exon 10 (also referred to as exon 11 in the literature), resulting in loss of the full-length transcript, and increased expression of a shorter in-frame transcript that lacks a large portion of exon 10 (referred to as del11q) (PMID: 17011978). This alternative in-frame transcript has been reported to occur naturally in healthy individuals (PMID: 24569164), and functional studies suggest that protein made from this transcript may retain residual function (PMID: 8972225, 11359908, 11431698, 16943438). The clinical significance of these findings is uncertain. A different variant (c.4096+3A>G), affecting the same consensus splice site, has been shown to result in the increased abundance of a naturally occurring BRCA1 isoform lacking exon 10, and a shortened in-frame splice variant that removes a large portion of this exon (PMID: 23239986). The shortened splice variants may retain residual function (PMID: 8972225, 16943438, 11359908, 11431698). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000048441 SCV000210164 likely pathogenic not provided 2018-09-20 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4096+1G>A or IVS10+1G>A, and consists of a G>A nucleotide substitution at the +1 position of intron 10 of the BRCA1 gene. This variant, previously reported as IVS11+1G>A using alternate nomenclature, destroys a canonical splice donor site and is predicted to cause abnormal gene splicing. Splicing assays have demonstrated that this variant results in the production of a shortened BRCA1 transcript lacking a large portion of exon 10, previously denoted exon 11, which is known as the BRCA1 delta11q isoform (Bonatti 2006). This shortened transcript encodes a truncated BRCA1 protein that lacks the nuclear localization signal and the DNA binding domain (Thakur 1997, Narod 2004, Borg 2010). BRCA1 c.4096+1G>A has been observed in individuals with breast, ovarian, or prostate cancer (Bonatti 2006, Manguoglu 2010, Tung 2015, Brianese 2017, Ibrahim 2018), and RNA studies in an ovarian cancer patient detected both normal length transcript as well as the shortened delta11q, with the shortened transcript being more abundant (Bonatti 2006). The delta 11q isoform has also been observed in control individuals and normal tissue (Thakur 1997, Bonatti 2006, Colombo 2014). In sum, although this canonical splice variant results in an abnormal protein product lacking key functional domains, the impact of this isoform on BRCA1 function cannot be predicted. We therefore consider this variant to be likely pathogenic.
Ambry Genetics RCV000162871 SCV000213358 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031146 SCV000296390 pathogenic Breast-ovarian cancer, familial 1 2015-09-24 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031146 SCV000325845 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000195364 SCV000591488 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-16 criteria provided, single submitter clinical testing
Color RCV000162871 SCV000683149 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-17 criteria provided, single submitter clinical testing
GeneKor MSA RCV000585685 SCV000693531 likely pathogenic Familial cancer of breast 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000790626 SCV000699108 uncertain significance not specified 2019-04-10 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4096+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. 3/5 computational tools predict this variant having a significant impact on normal splicing and abolishes a 5' splicing donor site. The variant allele was found at a frequency of 1.2e-05 in 245834 control chromosomes (gnomAD). The variant, c.4096+1G>A, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer and other cancers (Bonatti_2006, Manguoglu_2010 and Spugnesi_2016, Rebbeck_2018, Ibrahim_2018, Susswein_2016). These data indicate that the variant is very likely to be associated with disease. The experimental results indicated the delta10q was more abundant than the full-length transcript and there was a quantitative difference between proband and control, with the patient showing a reduced amount of full-length transcript (Bonatti_2006). Thus, increased amount of delta10q coupled with decreased amount of full-length transcript is a potential disease mechanism due to this variant. However, the ability of the protein product derived from the delta 10q transcript to impact BRCA1 function was not demonstrated in this study. The isoform delta10q would lack Serine-Rich domain (InterPro). Alternatively spliced BRCA1 isoforms that affect exon 10 have been described in minor amount in different human tissues (PMIDs: 9010228, 24569164) as well, and mouse studies have indicated that they may retain some residual function (PMIDs: 8972225, 11359908, 16943438). Co-occurrences with pathogenic variants have been reported in UMD (BRCA2 c.8249_8250delAG, p.Lys2750AsnfsX13, UMD database) and ClinVar (not specified), providing supporting evidence for a benign role. Eight clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2xVUS, 3xlikely pathogenic, 3xpathogenic). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Counsyl RCV000031146 SCV000786121 pathogenic Breast-ovarian cancer, familial 1 2018-02-28 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000585685 SCV000914331 uncertain significance Familial cancer of breast 2019-01-30 criteria provided, single submitter research
Sharing Clinical Reports Project (SCRP) RCV000031146 SCV000053746 pathogenic Breast-ovarian cancer, familial 1 2012-02-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031146 SCV000144971 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735546 SCV000863684 pathogenic Breast and/or ovarian cancer 2014-04-23 no assertion criteria provided clinical testing

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