Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4335_4338dupAGAA(p.Gln1447ArgfsTer16) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. E1446E) has been classified as Likely benign. 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 17-43082422-G-GTTCT is Pathogenic according to our data. Variant chr17-43082422-G-GTTCT is described in ClinVar as Pathogenic. ClinVar VariationId is 55172.Status of the report is reviewed_by_expert_panel, 3 stars.
Hereditary breast ovarian cancer syndromePathogenic:3
Jun 15, 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.4335_4338dupAGAA (p.Gln1447ArgfsX16) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Pro1464fsX2 and p.Ser1503X). The variant was absent in 246144 control chromosomes. c.4335_4338dupAGAA has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer. 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Oct 12, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55172). This variant is also known as c.4338_4339insAGAA p.Gln1447Argfs*16. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22798144, 28724667, 30287823). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1447Argfs*16) 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). -
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:2
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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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. -
The c.4335_4338dupAGAA pathogenic mutation, located in coding exon 11 of the BRCA1 gene, results from a duplication of AGAA at nucleotide position 4335, causing a translational frameshift with a predicted alternate stop codon (p.E1446Efs*17). This variant was identified in multiple individuals diagnosed with breast cancer (Kim H et al. Breast Cancer Res Treat. 2012 Aug;134(3):1315-26). 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. -
Aug 17, 2020
Color Diagnostics, LLC DBA Color Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant inserts 4 nucleotides in exon 12 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4454dupAGAA and c.4338_4339insAGAA in the literature. 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 reported in multiple East Asian individuals affected with breast cancer (PMID: 22798144, 25863477, 28724667, 29673794, 30287823). 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. -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group SPathogenic:1
Nov 15, 2013
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Gastric cancerPathogenic:1
Jul 01, 2021
Laboratory for Genotyping Development, RIKEN
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research
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not providedPathogenic:1
Dec 06, 2016
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This duplication of 4 nucleotides in BRCA1 is denoted c.4335_4338dupAGAA at the cDNA level and p.Gln1447ArgfsX16 (Q1447RfsX16) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is ATCC[dupAGAA]CAAA. The duplication causes a frameshift, which changes a Glutamine to an Arginine at codon 1447, and creates a premature stop codon at position 16 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.4335_4338dupAGAA, previously reported as BRCA1 4454dup4, has been identified in several Korean breast/ovarian cancer patients (Kim 2012, Kang 2015). We consider this variant to be pathogenic. -