Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1881_1884delCAGT(p.Ser628GlufsTer3) 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 17-43093646-TACTG-T is Pathogenic according to our data. Variant chr17-43093646-TACTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 54379.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093646-TACTG-T is described in Lovd as [Pathogenic]. Variant chr17-43093646-TACTG-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6
Mar 02, 2020
BRCAlab, Lund University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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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. -
May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Feb 08, 2008
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Jun 26, 2019
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.1881_1884delCAGT (p.Ser628Glufs*3) variant in the BRCA1 gene is predicted to introduce a premature translational termination codon. This variant was reported in multiple individuals affected with breast cancer or ovarian cancer from three unrelated families (PMID 10486320, 18006916) and is extremely rare in general population. Therefore, this c.1881_1884delCAGT (p.Ser628Glufs*3) variant in the BRCA1 gene is classified as pathogenic. -
not provided Pathogenic:4
May 27, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Dec 13, 2016
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jul 03, 2017
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This deletion of four nucleotides in BRCA1 is denoted c.1881_1884delCAGT at the cDNA level and p.Ser628GlufsX3 (S628EfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAGT[delCAGT]AGAA. The deletion causes a frameshift, which changes a Serine to a Glutamic Acid at codon 628, and creates a premature stop codon at position 3 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.1881_1884delCAGT, also known as BRCA1 2000del4 using alternate nomenclature, has been reported in association with hereditary breast and ovarian cancer (Gayther 1999, Ang 2007, Kwong 2016). We consider this variant to be pathogenic. -
Feb 24, 2015
Clinical Genetics and Genomics, Karolinska University Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:3
Sep 16, 2019
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.1881_1884delCAGT (p.Ser628GlufsX3) 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 allele was found at a frequency of 4e-06 in 251202 control chromosomes (gnomAD). c.1881_1884delCAGT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Sep 30, 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.Ser628Glufs*3) 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 present in population databases (rs80357567, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10486320, 28831036, 30702160). This variant is also known as 2000del4. ClinVar contains an entry for this variant (Variation ID: 54379). For these reasons, this variant has been classified as Pathogenic. -
Jun 12, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.Ser628fs variant in BRCA1 has been reported in at least 4 individuals with breast and or ovarian cancer and segregated with disease in 1 affected relative from 1 family (Gayther 1999, Breast Cancer Information (BIC) database). This va riant has also been identified in 1/33576 of Latino chromosomes by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80357567); however, however, this frequency is low enough to be consistent with the freque ncy of HBOC in the general population. This variant is predicted to cause a fram eshift, which alters the protein?s amino acid sequence beginning at position 628 and leads to a premature termination codon 3 amino acids downstream. This alter ation is then predicted to lead to a truncated or absent protein. Heterozygous l oss of function of the BRCA1 gene is an established disease mechanism in heredit ary breast and ovarian cancer (HBOC). In addition, the p.Ser628fs variant was cl assified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert pan el (ClinVar SCV000299662.2). In summary, this variant meets criteria to be class ified as pathogenic for HBOC in an autosomal dominant manner based upon the pred icted impact to the protein and low frequency in controls. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.1881_1884delCAGT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 1881 to 1884, causing a translational frameshift with a predicted alternate stop codon (p.S628Efs*3). This mutation has been identified in multiple individuals/families with hereditary breast and/or ovarian cancer (Gayther SA et al. Am. J. Hum. Genet. 1999 Oct;65:1021-9; Ang P et al. Cancer Epidemiol. Biomarkers Prev. 2007 Nov;16:2276-84). Of note, this alteration is also designated as 2000del4 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. -
Jan 25, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 4 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. This variant has been reported in an individual affected with breast cancer, and families affected by breast, ovarian, and colorectal cancer (PMID: 10486320, 32393398). This variant has been identified in 1/251202 chromosomes 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 Pathogenic:1
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Center for Precision Medicine, Meizhou People's Hospital