Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5102_5103delTG(p.Leu1701GlnfsTer14) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L1701L) has been classified as Uncertain significance. 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 17-43063922-TCA-T is Pathogenic according to our data. Variant chr17-43063922-TCA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 55401.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:4
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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Oct 05, 2006
Sharing Clinical Reports Project (SCRP)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Feb 20, 2004
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. -
Hereditary breast ovarian cancer syndromePathogenic:2
Apr 15, 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.Leu1701Glnfs*14) 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 a personal and/or family history of breast and/or ovarian cancer (PMID: 12204006, 16905680, 29446198). ClinVar contains an entry for this variant (Variation ID: 55401). 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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Breast and/or ovarian cancerPathogenic:1
Oct 10, 2011
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
The c.5102_5103delTG pathogenic mutation, located in coding exon 16 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 5102 to 5103, causing a translational frameshift with a predicted alternate stop codon (p.L1701Qfs*14). This variant has been identified in hereditary breast and ovarian cancer families world wide (Kang HC et al. Hum. Mutat., 2002 Sep;20:235; Simard J et al. J. Med. Genet., 2007 Feb;44:107-21; Cavallone L et al. Fam. Cancer, 2010 Dec;9:507-17; Kim H et al. Breast Cancer Res. Treat., 2012 Aug;134:1315-26; Belanger MH et al. J Ovarian Res, 2015 Mar;8:1; Briceño-Balcázar I et al. Colomb. Med., 2017 Jun;48:58-63; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Ryu JM et al. Breast Cancer Res. Treat., 2019 Jan;173:385-395; Kwon BS et al. Cancer Res Treat, 2019 Jul;51:941-950). Of note, this alteration is also designated as 5221delTG in the published 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. -
Breast carcinomaPathogenic:1
Aug 08, 2021
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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not providedUncertain:1
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Department of Pathology and Laboratory Medicine, Sinai Health System