17-43091434-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong
The ENST00000354071.8(BRCA1):n.4161G>A variant causes a non coding transcript exon 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. Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Consequence
ENST00000354071.8 non_coding_transcript_exon
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Fanconi anemia, complementation group SInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 4Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.4096+1G>A | splice_donor_variant, intron_variant | Intron 10 of 22 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.4096+1G>A | splice_donor_variant, intron_variant | Intron 10 of 22 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000120 AC: 3AN: 250952 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461660Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727094 show subpopulations
Age Distribution
GnomAD4 genome 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350 show subpopulations
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4Uncertain:5
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
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)
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.
not provided Pathogenic:1Uncertain:4
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.
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)
BRCA1: PVS1:Strong, PS3:Moderate, PM2:Supporting, BS2
Familial cancer of breast Uncertain:3
ACMG codes applied following ENIGMA VCEP rules: PVS1_M (RNA), PM2_SUP
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:1Uncertain:1
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.
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. RNA studies 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). Functional studies have reported conflicting findings in which the loss of exon 10 in ex vivo cell and murine animal models showed impaired DNA damage response and increased incidences of hyperplasia and spontaneous gynecological tumor (PMID: 11359908, 16943438), while other studies found retention of some BRCA1 functions (PMID: 8972225, 11359908, 11431698, 16943438). This variant has been reported in over 30 individuals affected with breast, ovarian and/or uterine cancer (PMID: 17011978, 21156238, 24131973, 25186627, 27328445, 29116469, 30728895, 32438681, 32885271, 32895300, 33801055, 37958491), 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 also has been reported in over a dozen unaffected individuals (PMID: 24569164, 37958491). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 0.297 from log(LR)=-0.526786506 for 8 carriers (PMID: 31853058). This variant has been identified in 3/250952 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Given the conflicting functional and clinical data and the possibility of reduced penetrance due to alternative splicing, additional clinical studies are needed to conclusively determine the role for this variant in disease. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Breast and/or ovarian cancer Pathogenic:1
Malignant tumor of breast Pathogenic:1
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
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
Hereditary breast ovarian cancer syndrome Uncertain:1
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, internal data). 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
Invasive Breast Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Negative Her2 Receptor: Negative
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at