rs80358170
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_007294.4(BRCA1):c.4987-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000625 in 1,600,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 splice_polypyrimidine_tract, intron
NM_007294.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.03391
2
Clinical Significance
Conservation
PhyloP100: 1.00
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_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
Variant 17-43067706-A-G is Benign according to our data. Variant chr17-43067706-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 125740.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.4987-11T>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000357654.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.4987-11T>C | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251202Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135784
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GnomAD4 exome AF: 0.00000621 AC: 9AN: 1448518Hom.: 0 Cov.: 29 AF XY: 0.0000111 AC XY: 8AN XY: 721342
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GnomAD4 genome 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 74310
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Mar 30, 2001 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 c.4987-11T>C variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in the following databases: dbSNP (ID: rs80358170) as "With other allele", in ClinVar (2x likely benign, 2x uncertain significance), and the BIC Database (1x, clincial importance unknown). The variant was not identified in the following databases: COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, ARUP Laboratories, or the Zhejiang University Database. The variant was identified in control databases in 1 of 246018 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the “Other” population in 1 of 5484 chromosomes (freq: 0.0002), while the variant was not observed in the African, Latino, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. A study using information theory to analyze splicing variants found that this variant may weaken the natural acceptor splice-site binding affinity (Mucaki 2011). The c.4987-11T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 03, 2023 | Variant summary: BRCA1 c.4987-11T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. RT-PCR analysis have showed the variant to have no impact on splicing (Wai_2020).The variant allele was found at a frequency of 4e-06 in 251202 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4987-11T>C has been reported in the literature without evidence for causality (example: Hondow_2011). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2020 | This variant is associated with the following publications: (PMID: 21523855, 21702907) - |
Hereditary cancer-predisposing syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 21, 2016 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -11
Find out detailed SpliceAI scores and Pangolin per-transcript scores at