Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.241C>T(p.Gln81Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q81Q) 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]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43104928-G-A is Pathogenic according to our data. Variant chr17-43104928-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 54565.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43104928-G-A is described in Lovd as [Pathogenic]. Variant chr17-43104928-G-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5Other:1
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
- -
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. -
Pathogenic, criteria provided, single submitter
clinical testing
Department of Medical Genetics, Oslo University Hospital
Jul 01, 2015
- -
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Mar 08, 2021
- -
Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
May 29, 2002
- -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Jul 08, 2021
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant has been reported in a family affected with breast cancer or ovarian cancer (PMID: 15382066). This variant is also known as c.360C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 54565). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln81*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, no assertion criteria provided
research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Jan 31, 2014
- -
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria provided
clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Sep 06, 2000
- -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Fulgent Genetics, Fulgent Genetics
Oct 31, 2018
- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Aug 15, 2023
- -
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
-
The p.Gln81X variant was identified in 1 of 338 proband chromosomes (frequency: 0.003) from individuals or families with Breast and or Ovarian cancer (Oros, 2004). The variant was also identified in dbSNP (ID: rs80357350) “With pathogenic allele”, HGMD, ClinVar database (sighted by BIC and invitae), the BIC database (3X with class 5 clinical importance), and UMD (5X as a causal variant). The p.Gln81X variant leads to a premature stop codon at position 81, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
The p.Q81* pathogenic mutation (also known as c.241C>T), located in coding exon 4 of the BRCA1 gene, results from a C to T substitution at nucleotide position 241. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This mutation has been reported in multiple families with hereditary breast and/or ovarian cancer (Oros KK et al. Int. J. Cancer 2004 Nov;112(3):411-9; Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457). Of note, this mutation is also designated as 360C>T in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -