Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS3PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5559C>G(p.Tyr1853*) 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 (★★★). ClinVar reports functional evidence for this variant: "SCV005547421: In multiple assays testing BRCA1 function, this variant showed functionally abnormal results (Dizin E et al. J Biol Chem, 2006 Aug" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y1853Y) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.
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):
BRCA1-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Our verdict: Pathogenic. The variant received 22 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.
PS3
PS3 evidence extracted from ClinVar submissions: SCV005547421: In multiple assays testing BRCA1 function, this variant showed functionally abnormal results (Dizin E et al. J Biol Chem, 2006 Aug;281:24236-46; Carvalho RS et al. PLoS One, 2014 May;9:e97766), including one that found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222).; SCV005838714: Experimental studies have shown that this premature translational stop signal affects BRCA1 function (PMID: 10811118, 11739404, 12400015, 21922593).
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43045711-G-C is Pathogenic according to our data. Variant chr17-43045711-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 55630.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.