Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3108dupT(p.Lys1037fs) 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]
Verdict is Pathogenic. Variant got 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 17-43092422-T-TA is Pathogenic according to our data. Variant chr17-43092422-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 54772.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
Nov 23, 2009
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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May 17, 2005
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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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. -
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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Mar 09, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:3
Feb 03, 2024
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.Lys1037*) 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 hereditary breast and ovarian cancer syndrome (PMID: 11802209, 29446198). This variant is also known as 3228insT. ClinVar contains an entry for this variant (Variation ID: 54772). For these reasons, this variant has been classified as Pathogenic. -
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
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Oct 29, 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.3108dupT (p.Lys1037X) 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 245844 control chromosomes (gnomAD). c.3108dupT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Meindl_2002, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
Nov 27, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The BRCA1 c.3108dup (p.Lys1037*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals and families with breast and/or ovarian cancer (PMIDs: 11802209 (2002), 29053726 (2017), 29446198 (2018), 33471991 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Jan 05, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal and/or family history consistent with Hereditary Breast and Ovarian Cancer syndrome (Meindl 2002, Rebbeck 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 3227dupT; This variant is associated with the following publications: (PMID: 11802209, 29446198, 28152038) -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.3108dupT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of T at nucleotide position 3108, causing a translational frameshift with a predicted alternate stop codon (p.K1037*). This alteration was detected in 3/989 unrelated individuals from a cohort of German breast/ovarian cancer families. (Meindl A et al. Int. J. Cancer, 2002 Feb;97:472-80). 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). Of note, this alteration is also known as designated as 3228insT in published literature. 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. -
Ovarian neoplasm Pathogenic:1
Dec 01, 2018
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne