chr17-43067607-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5074+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000206 in 1,453,788 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 Pathogenic (★★★).
Frequency
Consequence
NM_007294.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251352Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135878
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1453788Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3AN XY: 723708
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:9Other:1
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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 = 1 -
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A heterozygous 5' splice site variation in intron 16 of the BRCA1 gene that affects the invariant GT donor splice site of exon 16 (c.5074+1G>A). The observed variation (also known as IVS17+1G>A) has been previously reported in multiple breast and ovarian cancer patients [PMID: 29470806, 31528241, 17924331]. The variant has not been reported in the 1000 genomes, gnomAD V3.0 and gnomAD V2.1 databases. The in-silico prediction of the variant is damaging by Mutation Taster 2 tool. The reference base is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic. -
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This sequence change affects a donor splice site in intron 16 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80358053, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with triple-negative breast cancer (PMID: PMID: 17924331, 23593081, 25525159, 25724305, 22752604, 26911350, 27553291, 29470806, 29446198, 30209399, 31706072, 30093976, 31372034, 31528241, 31161121, 21990134, 27535533, 32341426, 32885271). This variant is also known as c.5074+1G>A . ClinVar contains an entry for this variant (Variation ID: 37629). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Experimental studies have shown that disruption of this splice site affects BRCA1 function (PMID: 30209399). Studies have shown that disruption of this splice site results in skipping of exon 16 and introduces a premature termination codon . The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
The invariant splice site c.5074+1G>A variant has been reported previously in heterozygous state in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Singh J et al). The variant is novel (not in any individuals) in gnomAD and in 1000 Genomes. This sequence change affects a donor splice site in intron 16 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Multifactorial likelihood analyses based on genetic evidence such as family history, co-segregation with disease, and co-occurrence with pathogenic variants predict that this variant is likely deleterious (Easton DF et al). Donor and acceptor splice site variants typically lead to a loss of protein function and loss-of-function variants in BRCA1 are known to be pathogenic (Baralle D et al). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay 2018); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Juwle 2012, Mannan 2016, Rashid 2016, Singh 2018); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 17924331, 23593081, 25525159, 25724305, 22752604, 26911350, 27553291, 29470806, 29446198, 30209399, 31706072, 30093976, 31372034, 31528241, 31161121, 21990134, 27535533, 32341426, 32885271) -
The BRCA1 c.5074+1G>A variant disrupts a canonical splice-donor site and interferes with normal BRCA1 mRNA splicing. This variant has been reported in the published literature in numerous individuals with breast and/or ovarian cancer (PMIDs: 29470806 (2018), 35377489 (2022)). The frequency of this variant in the general population, 0.000004 (1/251352 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.5074+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 15 of the BRCA1 gene. This mutation has been reported in a Pakistani proband with triple-negative breast cancer (Rashid MU et al. BMC Cancer 2016 Aug;16(1):673). Additionally, based on a multifactorial likelihood ratio model that integrates family history information as well as co-segregation and co-occurrence information, this alteration is calculated to have an odds ratio in favor of disease causality of 196:1 (Easton, DF et al. Am J Hum Genet. 2007 Nov;81(5):873-83). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay, GM. et al. Nature 2018 10;562(7726):217-222). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
This variant causes a G to A nucleotide substitution at the +1 position of intron 16 of the BRCA1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, a similar variant at this position c.5074+1G>T has been reported to cause aberrant splicing resulting in a frameshift splicing product and an in-frame deletion of part of the BRCT domain (PMID: 15345110, 24667779), therefore this variant is expected to result in an absent or disrupted protein product. A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in over 10 individuals affected with breast and/or ovarian cancer (PMID: 25452441, 27553291, 29470806, 31372034, 31528241, 31706072), and has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000377). In addition, a multifactorial likelihood model using health history and genetic data has suggested this variant have a high probability of being pathogenic (PMID: 17924331, 21990134). This variant has also been identified in 1/251352 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Variant summary: BRCA1 c.5074+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 a 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251352 control chromosomes. c.5074+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Singh_2018, Rashid_2019). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change affects a donor splice site in intron 16 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs80358053, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with triple-negative breast cancer (PMID: 27553291). This variant is also known as IVS17+1G>A. ClinVar contains an entry for this variant (Variation ID: 37629). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). Experimental studies have shown that disruption of this splice site affects BRCA1 function (PMID: 30209399). Studies have shown that disruption of this splice site results in skipping of exon 16, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
PM2_Supporting+PVS1+PS4_Moderate -
Malignant tumor of breast Pathogenic:1
The BRCA1 c.5074+1G>A variant was identified in 23 of 2120 proband chromosomes (frequency: 0.0108) from individuals or families with hereditary breast and ovarian cancer (Juwle 2012, Singh 2017). The variant was also identified in dbSNP (ID: rs80358053) as “With Pathogenic allele”, ClinVar (10x as pathogenic reviewed by expert panel), Clinvitae (4x as pathogenic), LOVD 3.0 (2x as pathogenic), BIC Database (3x), and ARUP Laboratories (as definitely pathogenic). The variant was not identified in Cosmic, MutDB, UMD-LSDB, or Zhejiang University Database. The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 1 of 246152 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the South Asian population in 1 of 30782 chromosomes (freq: 0.000032), but not observed in the African, Other, Latino, European (Non-Finnish), Ashkenazi Jewish, East Asian, or Finnish populations. Several papers which studied variants based on multifactorial probability based models classified the variant as pathogenic (Easton 2007, Lindor 2012). The c.5074+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at