Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4945_4947delAGAinsTTTT(p.Arg1649PhefsTer30) variant causes a frameshift, missense 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1649S) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 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 17-43070967-TCT-AAAA is Pathogenic according to our data. Variant chr17-43070967-TCT-AAAA is described in ClinVar as Pathogenic. ClinVar VariationId is 55327.Status of the report is reviewed_by_expert_panel, 3 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
BRCA1
NM_007294.4
MANE Select
c.4945_4947delAGAinsTTTT
p.Arg1649PhefsTer30
frameshift missense
Exon 15 of 23
NP_009225.1
BRCA1
NM_001407581.1
c.5011_5013delAGAinsTTTT
p.Arg1671PhefsTer30
frameshift missense
Exon 16 of 24
NP_001394510.1
BRCA1
NM_001407582.1
c.5011_5013delAGAinsTTTT
p.Arg1671PhefsTer30
frameshift missense
Exon 16 of 24
NP_001394511.1
Ensembl Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
BRCA1
ENST00000357654.9
TSL:1 MANE Select
c.4945_4947delAGAinsTTTT
p.Arg1649PhefsTer30
frameshift missense
Exon 15 of 23
ENSP00000350283.3
BRCA1
ENST00000471181.7
TSL:1
c.5008_5010delAGAinsTTTT
p.Arg1670PhefsTer30
frameshift missense
Exon 16 of 24
ENSP00000418960.2
BRCA1
ENST00000470026.6
TSL:1
c.4945_4947delAGAinsTTTT
p.Arg1649PhefsTer30
frameshift missense
Exon 15 of 23
ENSP00000419274.2
Frequencies
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:3
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Sep 02, 2022
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Oct 18, 2016
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:curation
Variant allele predicted to encode a truncated non-functional protein.
Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group SPathogenic:1
Jun 17, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
not providedPathogenic:1
Mar 14, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Frameshift 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 5064_5066delinsTTTT; This variant is associated with the following publications: (PMID: 15887246, 33646313)
The c.4945_4947delAGAinsTTTT pathogenic mutation, located in coding exon 14 of the BRCA1 gene, results from the deletion of 3 nucleotides and insertion of 4 nucleotides at positions c.4945 to c.4947, causing a translational frameshift with a predicted alternate stop codon (p.R1649Ffs*30). This alteration has been detected in multiple individuals diagnosed with breast and/or ovarian cancer (Bonadona V et al. Genes Chromosomes Cancer. 2005 Aug;43:404-13; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Donenberg T et al. Breast Cancer Res. Treat. 2016 Aug;159:131-8; Donenberg T et al. Breast Cancer Res Treat 2019 Apr;174(2):469-477). Of note, this mutation is also designated as 5064delAGA/insT4-ter1678 in published literature. 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.
Hereditary breast ovarian cancer syndromePathogenic:1