Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4357+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
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
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43082403-C-G is Pathogenic according to our data. Variant chr17-43082403-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
The c.4357+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 11 of the BRCA1 gene. This alteration was observed in an individual with a personal and family history of breast cancer within a Brazilian cohort of 349 probands considered to be at-risk for hereditary breast and ovarian cancer (HBOC) (Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481). 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). Two other alterations impacting the same donor site (c.4357+1G>A and c.4357+1G>T) have been reported in multiple individuals with a personal and/or family history consistent with HBOC syndrome, and have been shown to have a deleterious impact on splicing (Ambry internal data; Thomassen M et al. Breast Cancer Res. Treat. 2012 Apr;132:1009-23; Menéndez M et al. Breast Cancer Res. Treat. 2012 Apr;132(3):979-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
May 04, 2020
Color Diagnostics, LLC DBA Color Health
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant causes a G to C nucleotide substitution at the +1 position of intron 12 of the BRCA1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with breast cancer (PMID: 27741520, Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:1
Mar 25, 2013
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Hereditary breast ovarian cancer syndromePathogenic:1
Oct 28, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change affects a donor splice site in intron 12 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27741520, 29907814). This variant is also known as IVS13+1G>C. ClinVar contains an entry for this variant (Variation ID: 55177). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21735045, 24667779). For these reasons, this variant has been classified as Pathogenic. -