Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_007294.4(BRCA1):c.5194-18G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,610,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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]
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 17-43057153-C-A is Benign according to our data. Variant chr17-43057153-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 125803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Apr 02, 1998
- -
Likely benign, criteria provided, single submitter
clinical testing
Counsyl
Jun 01, 2016
- -
not specified Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jul 29, 2022
Variant summary: BRCA1 c.5194-18G>T alters a conserved nucleotide 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. One functional study did not find splicing defects (Thery_2011). The variant allele was found at a frequency of 4.8e-05 in 251484 control chromosomes, predominantly at a frequency of 0.00068 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.001), allowing no conclusion about variant significance. c.5194-18G>T has been reported in the literature as a VUS in individuals affected with Hereditary Breast And Ovarian Cancer (example, Judkins_2005, Fackenthal_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Four ClinVar submitters (evaluation after 2014) cite the variant as benign (n=1) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Benign:1
Benign, criteria provided, single submitter
clinical testing
GeneDx
Mar 03, 2015
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BRCA1-related disorder Benign:1
Likely benign, no assertion criteria provided
clinical testing
PreventionGenetics, part of Exact Sciences
Apr 26, 2019
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jan 05, 2016
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Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter