chr17-43091434-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPP5_Strong
The NM_007294.4(BRCA1):c.4096+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 splice_donor, intron
NM_007294.4 splice_donor, intron
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.23
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.61248213 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5, offset of 45, new splice context is: gaaGTgagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PP5
Variant 17-43091434-C-T is Pathogenic according to our data. Variant chr17-43091434-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 37565.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=13, Likely_pathogenic=3}. Variant chr17-43091434-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-43091434-C-T is described in Lovd as [Pathogenic]. Variant chr17-43091434-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250952Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135658
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461660Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727094
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GnomAD4 genome 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:9Uncertain:16
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Feb 13, 2012 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Medical and Surgical Sciences, University of Bologna | Sep 01, 2023 | PVS1_RNA(Moderate)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) - |
| Uncertain significance, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 12, 2018 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 28, 2018 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 30, 2024 | - - |
not provided Pathogenic:1Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | BRCA1: PVS1:Strong, PS3:Moderate, PM2:Supporting, BS2 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 11, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2024 | Canonical splice variant demonstrated to result in a shortened BRCA1 transcript lacking a large portion of exon 10, previously denoted exon 11, which is known as the delta11q isoform, with inconclusive functional impact (PMID: 8972225, 17011978, 24569164)); The resulting delta 11q isoform has also been observed in control individuals and normal tissue, therefore the clinical significance of this shortened transcript is indeterminate and this variant may confer risks lower than a typical BRCA1 pathogenic variant (PMID: 8972225, 17011978, 24569164); Observed in individuals with breast, ovarian, or prostate cancer (PMID: 17011978, 21156238, 25186627, 29116469, 29433453, 32438681, 30728895); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4215+1G>A and IVS11+1G>A; This variant is associated with the following publications: (PMID: 25525159, 37958491, 35534704, 11162473, 17011978, 8972225, 16943438, 11359908, 24569164, 27328445, 21156238, 28588062, 21523855, 28152038, 26269718, 24131973, 29433453, 29116469, 16267036, 29907814, 29922827, 29446198, 25186627, 28726806, 26681312, 32885271, 32438681, 30728895, 30675319, 31209999, 15343273, 20104584, 22737296, 32322110, 31341520, 36331686, 35150867, 30720243, 35132179, 31159747, 28888541, 37851290, 39103848, 36993400) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 11, 2024 | The BRCA1 c.4096+1G>A variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 17011978 (2006), 21156238 (2010), 27328445 (2016), 29116469 (2018), 30675319 (2019), 32438681 (2020), and 32885271 (2021), 35534704 (2021), 35534704 (2022)) and prostate cancer (PMID: 29433453 (2018)). This variant has been proven to result in production of a naturally occurring in-frame transcript ‘delta 11’ (PMID: 17011978 (2006), ENIGMA Consortium (Evidence-based Network for the Interpretation of Germline Mutant Alleles, http://www.enigmaconsortium.org/)) and may not exhibit the clinical characteristics of a standard high-risk pathogenic BRCA1 variant. The 'delta 11' isoform of BRCA1 has been shown to be naturally occurring and one of the most abundant alternatively spliced isoforms found in normal tissues, such as breast and lymphocytes (PMID: 24569164 (2014)). In addition, functional studies have indicated that BRCA1 isoforms without BRCA1 exon 11 are partially or fully functional (PMID: 8972225 (1997), 11359908 (2001), 16943438 (2006)). The frequency of this variant in the general population, 0.000026 (3/113500 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Familial cancer of breast Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 09, 2024 | ACMG codes applied following ENIGMA VCEP rules: PVS1_M (RNA), PM2_SUP - |
| Uncertain significance, criteria provided, single submitter | research | A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center | Jan 30, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | May 06, 2021 | This sequence change occurs 1 base after exon 10 of the BRCA1 gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. 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 (PMID: 17011978). The delta 11q isoform has also been observed in control individuals and normal tissue (PMID: 8972225, 11359908, 11431698, 16943438). Moreover, functional studies in mice have indicated that they may retain some residual function of BRCA1 delta11q isoform (PMID: 8972225, 16943438, 11359908, 11431698). This variant is also known as IVS11+1G>A in the literature and it has been described in individuals affected with ovarian (PMID: 17011978) and breast cancer (PMID: 27328445). The mutation database ClinVar contains entries for this variant (Variation ID: 37565). In summary, this sequence change has been shown to impact mRNA splicing and is predicted to be deleterious. However, there are some indications that BRCA1 protein missing exon 10 may retain residual function. For these reasons, this variant has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 11, 2024 | The c.4096+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 9 of the BRCA1 gene. This alteration has been reported in several triple-negative breast and ovarian cancer patients (Bonatti F et al. Cancer Genet Cytogenet. 2006 Oct 15;170(2):93-101; Brianese RC et al. Breast Cancer Res. Treat., 2018 Feb;167:803-814; Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 Mar;147:871-879), as well as multiple cohorts of ancestrally diverse of individuals undergoing genetic testing for hereditary cancer risk (Santonocito C et al. Cancers (Basel). 2020 May;12; Susswein LR et al. Genet. Med. 2016 08;18:823-32; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535; Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). RNA studies showed that this alteration leads to a partial exon 11 (CDS9) skipping event-termed Δ11q (Ambry internal data; Bonatti F et al. Cancer Genet Cytogenet. 2006 Oct 15;170(2):93-101). However, these transcripts are also naturally occurring in humans and there is discordance among studies regarding the impact on the encoded proteins with respect to cellular localization and their role in hereditary cancer (Colombo M et al. Hum. Mol. Genet. 2014; 23(14):3666–3680; Thakur S et al. Mol. Cell. Biol. 1997 Jan; 17(1):444-52; Huber LJ et al. Mol. Cell. Biol. 2001 Jun; 21(12):4005-15). Of note, this alteration is also designated as IVS11+1G>A in published literature. Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 17, 2023 | This variant causes a G>A nucleotide substitution at the +1 position of intron 10 of the BRCA1 gene. This variant is also known as IVS11+1G>A and c.4215+1G>A. An RNA study found the variant enhanced the use of a naturally occurring alternative splice donor site in exon 10 (alternative transcript delta 11q), resulting in an in-frame deletion (PMID: 17011978, 24569164). This variant has been reported in at least six individuals affected with breast or ovarian cancer (PMID: 17011978, 21156238, 24131973, 25186627, 27328445, 29116469, 30728895, 32438681, 32885271, 32895300, 33801055), an individual affected with prostate cancer (PMID: 29433453) and in suspected hereditary breast and ovarian cancer families (PMID: 16267036, 24065114, 30675319, 31159747, 31209999). This variant has been identified in 3/250952 chromosomes in the general population by the Genome Aggregation Database (gnomAD). It has also been reported that this variant may not exhibit the clinical characteristics of a standard high-risk pathogenic BRCA1 variant, presumably due to alternative splicing events that may ameliorate the deleterious impact of this variant (PMID: 32322110; ClinVar variation ID 37565). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Apr 23, 2014 | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The c.4096+1G>A variant was identified in an individual with ovarian cancer from a hereditary breast and ovarian cancer family (Bonatti 2006). The variant was also identified in dbSNP (ID: rs80358178) “With pathogenic allele”, HGMD, LOVD, UMD (5X as a causal variant), and the BIC database (5X with clinical importance). The c.4096+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the 5' splice consensus sequence. Three in silico or computational prediction software programs (MaxEntScan, NNSPLICE, HumanSpliceFinder) predict a greater than 10% difference in splicing. In addition, RNA analysis of a patient with the variant determined that the variant resulted in a skipping of exon 11, with reduced expression of full-length transcript as compared to normal control DNA (Bonatti 2006). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 30, 2021 | 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. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5 splicing donor site. Experimental evidence supports these predictions demonstrating the presence of a BRCA1 isoform that lacks a large portion of exon 10 (delta 10q) in a patient's cDNA (Bonatti_2006). Results indicated the delta 10q 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. Thus, increased amount of delta 10q coupled with decreased amount of full-length transcript is a potential disease mechanism attributed 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 delta 10q would lack the Serine-Rich domain (InterPro). Alternatively spliced BRCA1 isoforms that affect exon 10 have been described in minor amounts in different human tissues (PMIDs: 9010228, 24569164) and mouse studies have indicated that they may retain some residual function (PMIDs: 8972225, 11359908, 16943438). The variant allele was found at a frequency of 1.2e-05 in 250952 control chromosomes (gnomAD). c.4096+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer and other cancers (e.g. Bonatti_2006, Brianese_2018, Ibrahim_2018, Manguoglu_2010, Rebbeck_2018, Spugnesi_2016, Susswein_2016) but it was also detected in unaffected members of families reported with cases of breast cancer (e.g. Servais_2016, Slavin_2019). Co-occurrences with another pathogenic variant have been reported (UMD: BRCA2 c.8249_8250delAG, p.Lys2750AsnfsX13; ClinVar: BRCA1 unspecified variant). Eleven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (n=6) and as uncertain significance (n=5, including ENIGMA expert panel). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 26, 2024 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change affects a donor splice site in intron 10 of the BRCA1 gene. It is expected to disrupt RNA splicing. This variant is present in population databases (rs80358178, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with BRCA1-related conditions (PMID: 17011978, 21156238, 27328445, 29116469, 29433453, 29446198, 32885271). ClinVar contains an entry for this variant (Variation ID: 37565). Experimental studies have shown that disruption of this splice site 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, Invitae). 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. - |
Breast carcinoma Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 08, 2021 | Invasive Breast Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Negative Her2 Receptor: Negative - |
Computational scores
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
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Pathogenic
FATHMM_MKL
Uncertain
D
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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