rs587780863
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_007294.4(BRCA1):c.4653T>C(p.Ser1551=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,948 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 Likely benign (★★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000075 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 synonymous
NM_007294.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.302
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 Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
Variant 17-43074353-A-G is Benign according to our data. Variant chr17-43074353-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136549.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074353-A-G is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.302 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.4653T>C | p.Ser1551= | synonymous_variant | 14/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.4653T>C | p.Ser1551= | synonymous_variant | 14/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152204Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251252Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135784
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GnomAD4 exome AF: 0.0000753 AC: 110AN: 1461744Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53AN XY: 727176
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ClinVar
Significance: Likely benign
Submissions summary: Benign:12
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:4
Likely benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 29, 2017 | Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Sep 11, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 24, 2017 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 27, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2015 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 12, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 18, 2017 | Variant summary: The BRCA1 c.4653T>C (p.Ser1551Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing, which is supported by the minigene-based splicing assay results in Houdayer et al 2012. This variant was found in 3/121366 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as likely benign. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Ser1551= variant was identified in the literature; however the frequency of this variant in an affected population was not provided (Houdayer 2012, Judkins 2005). The variant was also identified in dbSNP (ID: rs587780863) as With Likely benign allele, ClinVar (as likely benign by ENIGMA, Color, Integrated Genetics, Ambry Genetics, Invitae, and Counsyl; and as benign by GeneDx and Michican Medical Genetics Laboratories), LOVD 3.0 (as benign and as VUS). The variant was identified in control databases in 7 of 277012 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (Non-Finnish) population in 7 of 126516 chromosomes (freq: 0.000055), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser1551= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at