Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2443delA(p.Ile815PhefsTer31) 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 17-43093087-AT-A is Pathogenic according to our data. Variant chr17-43093087-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 54572.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093087-AT-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4
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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Jan 27, 2024
Baylor Genetics
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. -
Feb 08, 2010
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:3
Apr 05, 2021
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.2443delA (p.Ile815PhefsX31) 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. The variant was absent in 250656 control chromosomes. c.2443delA has been reported in the literature in individuals affected with Hereditary Breast and/or Ovarian Cancer as well as in at-least one individual within a cohort of adult biobank participants who underwent exome sequencing (example, Judkins_2005, Manickam_2018, Zhu_2020). Three clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Aug 04, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.Ile815fs variant in BRCA1 has been reported in 1 individual with breast an d ovarian cancer (Breast Cancer Information Core (BIC) database). It was also ab sent from large population studies. This variant is predicted to cause a framesh ift, which alters the protein?s amino acid sequence beginning at position 815 an d leads to a premature termination codon 31 amino acids downstream. This alterat ion is then predicted to lead to a truncated or absent protein. Heterozygous los s of function of the BRCA1 gene is an established disease mechanism for heredita ry breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (Cl inVar SCV000299769.2). In summary, this variant meets our criteria to be classif ied as pathogenic for autosomal dominant HBOC. -
Dec 24, 2023
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.Ile815Phefs*31) 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 variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 54572). For these reasons, this variant has been classified as Pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: curation
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Dec 13, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.2443delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2443, causing a translational frameshift with a predicted alternate stop codon (p.I815Ffs*31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
not provided Pathogenic:1
Jun 09, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The BRCA1 c.2443del; p.Ile815PhefsTer31 variant (rs80357598, ClinVar variation ID: 54572) is reported in the literature in exome cohorts with a family history of breast and/or ovarian cancer (Manickam 2018, Zhu 2020). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Manickam K et al. Exome Sequencing-Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants. JAMA Netw Open. 2018 Sep 7;1(5):e182140. PMID: 30646163. Zhu Q et al. Whole-exome sequencing of ovarian cancer families uncovers putative predisposition genes. Int J Cancer. 2020 Apr 15;146(8):2147-2155. PMID: 31265121. -