Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_007294.4(BRCA1):c.671-18_671-16delATT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 17-43094875-AAAT-A is Benign according to our data. Variant chr17-43094875-AAAT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 125907.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6}.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Mendelics
May 28, 2019
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Jun 24, 2016
- -
Likely benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Nov 20, 2023
- -
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
-
- -
not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Aug 08, 2022
Variant summary: BRCA1 c.671-18_671-16delATT results in the deletion of three non-conserved nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.5e-06 in 219956 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.671-18_671-16delATT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, co-occurring with pathogenic variants (BRCA1 c.4964_4982del19, p.Ser1655TyrfsX16; BARD1 c.772delA, p.Ile258X; BIC database, Judkins_2005, Turchiano_2022). These data provide evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three laboratories classified the variant as likely benign and one classified it as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter
clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Aug 15, 2023
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Uncertain significance, no assertion criteria provided
research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Jan 31, 2014
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Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Aug 29, 2016
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Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter