Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM4
The NM_007294.4(BRCA1):c.5565_5573delACCCCAGAT(p.Pro1856_Ile1858del) variant causes a disruptive 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 Uncertain significance.
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: Likely_pathogenic. The variant received 6 ACMG points.
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 61 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_007294.4.
Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:3
Feb 27, 2012
Sharing Clinical Reports Project (SCRP)
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Jun 02, 2023
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Jun 07, 2018
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
not specifiedUncertain:1
Jan 20, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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. -
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 (QIP) between codons 1857 and 1859. These amino acid positions are not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. -
Hereditary breast ovarian cancer syndromeUncertain:1
Nov 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 34271787). ClinVar contains an entry for this variant (Variation ID: 37682). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -