Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM4
The NM_007294.4(BRCA1):c.5565_5573del(p.Gln1857_Pro1859del) variant causes a inframe deletion 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I1855I) has been classified as Likely benign.
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 16 uncertain in NM_007294.4
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM4
?
PM4 - Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
Nonframeshift variant in NON repetitive region in NM_007294.4.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3
Uncertain significance, criteria provided, single submitter
clinical testing
Baylor Genetics
Jun 02, 2023
- -
Uncertain significance, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Feb 27, 2012
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Jun 07, 2018
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not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jan 20, 2022
Variant summary: BRCA1 c.5565_5573delACCCCAGAT (p.Gln1857_Pro1859del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant was absent in 250832 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5565_5573delACCCCAGAT has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome (Tariq_2021). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Oct 21, 2019
The c.5565_5573delACCCCAGAT variant (also known as p.Q1857_P1859DEL) is located in coding exon 22 of the BRCA1 gene. This variant results from an in-frame ACCCCAGAT deletion of between nucleotide positions 5565 and 5573. This results in the deletion of 3 residues between codons 1857 and 1859. These amino acid positions are not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Nov 25, 2022
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 37682). This variant has been observed in individual(s) with breast cancer (PMID: 34271787). This variant is not present in population databases (gnomAD no frequency). This variant, c.5565_5573del, results in the deletion of 3 amino acid(s) of the BRCA1 protein (p.Gln1857_Pro1859del), but otherwise preserves the integrity of the reading frame. -