Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP6_Very_Strong
The NM_007294.4(BRCA1):c.135-15_135-12delCTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000192 in 1,560,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar 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_benign. Variant got -6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 17-43106544-TAAAG-T is Benign according to our data. Variant chr17-43106544-TAAAG-T is described in ClinVar as [Likely_benign]. Clinvar id is 240772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43106544-TAAAG-T is described in Lovd as [Benign].
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jun 13, 2018
- -
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Jun 23, 2021
- -
not specified Benign:1
Benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jul 04, 2022
Variant summary: BRCA1 c.135-15_135-12delCTTT alters four 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. The variant was absent in 246264 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.135-15_135-12delCTTT has been reported in the literature as a "rare-neutral variant" in individuals affected with Hereditary Breast and Ovarian Cancer (example, Judkins_2005, Vreeswijk_2008, Mohammadi_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant(s) has been reported at our laboratory (BRCA2 c.7758G>A, p.W2586X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on splicing and showed no damaging effect of this variant on RNA splicing (Vreeswijk_2008). Four 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 likely benign. Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Jan 24, 2023
See Variant Classification Assertion Criteria. -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter