Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2351C>A(p.Ser784*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S784S) has been classified as Likely benign. 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 17-43093180-G-T is Pathogenic according to our data. Variant chr17-43093180-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 487430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.2351C>A
p.Ser784*
stop_gained
Exon 10 of 23
NP_009225.1
BRCA1
NM_001407581.1
c.2351C>A
p.Ser784*
stop_gained
Exon 10 of 24
NP_001394510.1
BRCA1
NM_001407582.1
c.2351C>A
p.Ser784*
stop_gained
Exon 10 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.2351C>A
p.Ser784*
stop_gained
Exon 10 of 23
ENSP00000350283.3
BRCA1
ENST00000471181.7
TSL:1
c.2351C>A
p.Ser784*
stop_gained
Exon 10 of 24
ENSP00000418960.2
BRCA1
ENST00000470026.6
TSL:1
c.2351C>A
p.Ser784*
stop_gained
Exon 10 of 23
ENSP00000419274.2
Frequencies
GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461582
Hom.:
0
Cov.:
41
AF XY:
0.00
AC XY:
0
AN XY:
727074
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26122
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86214
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53286
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111922
Other (OTH)
AF:
0.00
AC:
0
AN:
60384
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:1
Mar 22, 2017
Counsyl
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
not providedPathogenic:1
Jul 11, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Not found in the total gnomAD dataset, and the data is high quality (0/282034 chr).
The p.S784* pathogenic mutation (also known as c.2351C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 2351. This changes the amino acid from a serine to a stop codon within coding exon 9. 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.