Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2901_2902dupTC(p.Pro968LeufsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). 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 17-43092628-G-GGA is Pathogenic according to our data. Variant chr17-43092628-G-GGA is described in ClinVar as Pathogenic. ClinVar VariationId is 91602.Status of the report is reviewed_by_expert_panel, 3 stars.
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
PVS1, PM5_PTC_Strong c.2901_2902dup, located in exon 10 (11 in BIC nomenclature) of the BRCA1 gene, consists in the duplication of two nucleotides, causing a translational frameshift with a predicted alternate stop codon, p.(Pro968Leufs*33). This alteration is expected to result in loss of function because the resulting coding sequence is not preserved (PVS1, PM5_PTC_Strong). It is not present in the population database gnomAD v2.1.1, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. This variant has been reported in the ClinVar database (10x Pathogenic) and in LOVD database (6x pathogenic, 1x not classified) and classified as a pathogenic variant in BRCA Exchange database (“2016-10-18: Variant allele predicted to encode a truncated non-functional protein”). Based on currently available information, the variant c.2901_2902dup is classified as a pathogenic variant according to ClinGen-BRCA1 and BRCA2 Guidelines version 1.0.0. -
Oct 17, 2024
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.2901_2902dupTC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TC at nucleotide position 2901, causing a translational frameshift with a predicted alternate stop codon (p.P968Lfs*33). This mutation has been detected in multiple individuals with personal and/or family histories of breast and ovarian cancer, and has been seen specifically in families of Northern Spanish (Asturian) descent, suggesting a possible founder effect (Blay P et al. BMC Cancer, 2013 May;13:243; Salgado J et al. Oncol Lett, 2013 Sep;6:725-727; Cardoso FC et al. Hum. Genomics, 2018 08;12:39; Ruiz de Sabando A et al. BMC Cancer, 2019 Nov;19:1145). 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, 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. -
Mar 04, 2022
Sema4, Sema4
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation
- -
Jan 25, 2021
Color Diagnostics, LLC DBA Color Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant inserts 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 23683081, 24137399, 25136594, 30103829, 31771539). 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 Pathogenic. -
Hereditary breast ovarian cancer syndromePathogenic:2
Jan 06, 2025
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.Pro968Leufs*33) 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 is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 23683081, 24137399, 25136594). This variant is also known as c.2901insCT and c.2900_2901dupCT. ClinVar contains an entry for this variant (Variation ID: 91602). For these reasons, this variant has been classified as Pathogenic. -
Jul 31, 2018
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: BRCA1 c.2901_2902dupTC (p.Pro968LeufsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246162 control chromosomes (gnomAD). The variant, c.2901_2902dupTC (also known as 3020insCT, 2901incCT, 2900_2901dupCT) has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, including in one family where it segregated with disease (Blay_2013, Ruiz_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Fanconi anemia, complementation group SPathogenic:1
May 01, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System