17-43076487-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.4484+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 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
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7
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A mutation that affects a splice site in the BRCA1 gene was detected in this specimen. This mutation is considered as “likely pathogenic”. Pathogenic mutations in the BRCA1 gene cause Hereditary Breast/Ovarian Cancer syndrome (HBOC). -
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Hereditary breast ovarian cancer syndrome Pathogenic:3
The c.4484+1G>A variant in BRCA1 (referred to as IVS14+1G>A by some studies) has been reported in at least 3 individuals with BRCA1-associated cancers (Mannan e t al. 2016, Juwle et al. 2012, Perkowska et al. 2003). It has also been reported by other clinical laboratories in ClinVar (Variation ID# 37596) and was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been shown to lead to skipping of exon 14 (Xiong et al. 2015, Steffensen et al. 2014), leading to a frameshift and premature termination 10 amino acids downstream of exon 13 (Houdayer et al. 201 2, Perkowska et al. 2003). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as path ogenic for HBOC in an autosomal dominant manner based upon impact to the prote in, absence from controls and functional evidence. -
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This sequence change affects a donor splice site in intron 13 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and ovarian cancer and/or early-onset breast cancer (PMID: 12673801, 22752604). This variant is also known as IVS14+1G>A; 4603+1G>A. ClinVar contains an entry for this variant (Variation ID: 37596). Studies have shown that disruption of this splice site results in skipping of exon 13, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 12673801, 22505045, 24667779; Invitae). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
Canonical splice site variant demonstrated to result in exon skipping leading to premature protein truncation, in a gene for which loss of function is a known mechanism of disease (PMID: 12673801, 22505045, 24667779); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 17997147, 22752604, 29254167, 30441849, 29470806, 29752822); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS14+1G>A and 4603+1G>A; This variant is associated with the following publications: (PMID: 22505045, 17997147, 25525159, 29752822, 28888541, 26843898, 27167707, 22752604, 29470806, 26911350, 12673801, 24667779, 29254167, 29805665, 30441849, 29446198, 31159747, 31209999, 31447099, 31825140, 30787465, 37852034, 38439815) -
This variant disrupts a canonical splice-donor site and interferes with normal BRCA1 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals and families with hereditary breast and/or ovarian cancer (PMIDs: 31825140 (2019), 29752822 (2018), 29470806 (2018), 26911350 (2016), 22752604 (2012), 17997147 (2008), 12673801 (2003)). Functional studies have demonstrated that this variant leads to exon 14 skipping (PMIDs: 24667779 (2014), 22505045 (2012), 12673801 (2003)). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant causes a G>A nucleotide substitution at the +1 position of intron 13 of the BRCA1 gene. Functional RNA studies have shown that this variant causes out-of-frame skipping of exon 13, resulting in premature truncation (PMID: 12673801, 22505045, 24667779). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 12673801, 22752604). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
The c.4484+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the BRCA1 gene. This mutation has been previously identified in multiple individuals affected with breast and/or ovarian cancer (Perkowska M et al. Hum. Mutat. 2003 May; 21(5):553-4; Juwle A and Saranath D. Med. Oncol. 2012 Dec; 29(5):3272-81; Mannan AU et al. J. Hum. Genet. 2016 Jun;61:515-22; Brozek I et al. Gynecol. Oncol. 2008 Feb;108:433-7). Additionally, RT-PCR analysis, transcript analysis, and a mini-gene splicing assay have shown that this alteration leads to a skipping of coding exon 12, leading to a frameshift and an alternate stop codon (Ambry internal data; Perkowska M et al. Hum. Mutat. 2003 May; 21(5):553-4. Houdayer C et al. Hum. Mutat. 2012 Aug; 33(8):1228-38; Steffensen AY et al. Eur. J. Hum. Genet. 2014 Dec; 22(12):1362-8). Of note, this alteration is also designated as IVS14+1G>A in published literature. In addition to the clinical and functional data presented in the literature, 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
BRCA1-related cancer predisposition Pathogenic:1
This variant causes a G>A nucleotide substitution at the +1 position of intron 13 of the BRCA1 gene. RNA studies have shown that this variant causes out-of-frame skipping of exon 13, resulting in premature truncation (PMID: 12673801, 22505045, 24667779). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast and//or ovarian cancer (PMID: 12673801, 22752604, 29470806, 29752822, 31825140). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
Malignant tumor of breast Pathogenic:1
The BRCA1 c.4484+1G>A variant was identified in 2 of 220 proband chromosomes (frequency: 0.009) from individuals or families with breast and/or ovarian cancers, and was not identified in 100 control chromosomes analyzed from healthy individuals (Perkowska 2003, Juwle 2012). The variant was also identified in dbSNP (ID: rs80358063) “With Pathogenic allele”, HGMD, LOVD, the BIC database (2X with clinical importance), UMD (1X as a causal variant), the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports), and Gene Insight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, classified as “pathogenic” by a clinical laboratory). The c.4484+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence; in addition, five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Furthermore, RNA transcript analysis of the variant demonstrated a skipping of exon 14 by analysis from an affected proband’s blood (Perkowska 2003), and by analysis from cells lines transfected with the variant (Houdayer 2012, Steffensen 2014). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Familial cancer of breast Pathogenic:1
This sequence change occurs 1 base after exon 14 of the BRCA1 gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. This mutation is expected to result in incorrect splicing, alteration in the reading frame and a truncated protein. The mutation database Clinvar contains entries for this variant (Variation ID:37596)In summary, this is a rare sequence change that is expected to affect the BRCA1 protein and cause disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at