rs398122636
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1512_1513insT(p.Lys505Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.142
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-43094018-T-TA is Pathogenic according to our data. Variant chr17-43094018-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 91554.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.1512_1513insT | p.Lys505Ter | frameshift_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.1512_1513insT | p.Lys505Ter | frameshift_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 28, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 12, 2023 | This nonsense variant causes the premature termination of BRCA1 protein synthesis. 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 an affected individual with ovarian cancer (PMID: 24728189 (2014)). The variant was also found in a family in a worldwide BRCA1/BRCA2 screening study (PMID: 29446198 (2018)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1631dup; Observed in an individual with serous ovarian cancer (Song et al., 2014) and similar variants resulting in the same protein change, Lys505Ter, have been reported in association with hereditary breast and ovarian cancer (Palmieri et al., 2002; Palomba et al., 2005; Jang et al., 2012; Kim et al., 2012); This variant is associated with the following publications: (PMID: 24728189, 12453858, 22217648, 16047344, 22798144) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 16, 2017 | Variant summary: The BRCA1 c.1512dupT (p.Lys505X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1518delG (p.Arg507fsX25), c.1556delA (p.Lys519fsX13), c.1621C>T (Gln541X)). The variant has been reported in an affected individual in the literature (Song 2014). Other variants affecting the same codon and causing an equivalent protein level change as the variant of interest have also been found in HBOC patients (Palomba 2005, Park 2017). This variant is absent in 279850 control chromosomes (in gnomAD and publication(s)). In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change creates a premature translational stop signal (p.Lys505*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 91554). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 26, 2023 | The c.1512dupT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of T at nucleotide position 1512, causing a translational frameshift with a predicted alternate stop codon (p.K505*). In one case control study, this alteration was detected in 1/2222 individuals with invasive epithelial ovarian cancer and 0/1528 matched controls. (Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9). Additionally, this alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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