Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3511A>T(p.Lys1171*) 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. K1171K) 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 17-43092020-T-A is Pathogenic according to our data. Variant chr17-43092020-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 183177.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:3
Sep 08, 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. -
Feb 11, 2015
Institute of Human Genetics, Medical University Innsbruck
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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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
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BRCA1-related disorderPathogenic:1
Apr 18, 2024
PreventionGenetics, part of Exact Sciences
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
The BRCA1 c.3511A>T variant is predicted to result in premature protein termination (p.Lys1171*). This variant was reported in a large cohort of families tested for BRCA1 variants (Rebbeck et al. 2018. PubMed ID: 29446198). This variant has not been reported in a large population database, indicating this variant is rare. It is classified as pathogenic by several labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/183177/). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
The p.K1171* pathogenic mutation (also known as c.3511A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 3511. This changes the amino acid from a lysine to a stop codon within coding exon 9. This alteration was identified in 2/238 unrelated Austrian individuals with suspected hereditary breast and ovarian cancer (Pölsler L et al. Eur. J. Hum. Genet. 2016 Feb;24:258-62). This alteration was also 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. -
Hereditary breast ovarian cancer syndromePathogenic:1
May 29, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change creates a premature translational stop signal (p.Lys1171*) 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 has been observed in individuals affected with breast or ovarian cancer (PMID: 26014432). ClinVar contains an entry for this variant (Variation ID: 183177). This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. -