Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001407889.1(BRCA1):c.-171A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,138 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 17-43115726-T-G is Benign according to our data. Variant chr17-43115726-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37402.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=6, not_provided=1}.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3Benign:1Other:1
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
- -
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Feb 20, 2004
- -
Uncertain significance, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
May 03, 2010
- -
Likely benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Sep 04, 2023
This missense variant replaces lysine with threonine at codon 45 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies reported conflicting variant impact on BRCA1 function from loss of ubiquitin ligase activity (PMID: 16403807) to no impact on a haploid human cell proliferation assay (PMID: 30209399). This variant has been observed in an individual affected with unilateral breast cancer (PMID: 20104584) and an individual age 70 years or older without cancer (FLOSSIES database). This variant also has been reported in a multifactorial analysis with family history likelihood ratio for pathogenicity of 0.0387 (PMID: 31131967). This variant has been identified in 2/250502 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Feb 19, 2016
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not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Jun 19, 2020
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Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Jul 23, 2019
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20104584, 30209399, 21520273, 15235020, 16403807, 21523855, 000, 19543972, 16267036, 15385441, 25823446, 24489791, 33087888) -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Mar 02, 2023
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Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 19, 2019
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not specified Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Aug 05, 2024
Variant summary: BRCA1 c.134A>C (p.Lys45Thr) results in a non-conservative amino acid change located in the Zinc finger, RING-type (IPR001841) and Zinc finger, C3HC4 RING-type (IPR018957) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation 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 8e-06 in 250502 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.134A>C has been reported in the literature (e.g. Borg 2010). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.26_26delC, p.Pro9Glnfs, BIC database), providing supporting evidence for a benign role. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. In another in-vitro assay, this variant was shown to decrease the ubiquitin ligase activity (Morris_2006, Starita_2015). The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 20104584, 15235020, 21520273, 16403807, 25823446, 30209399). ClinVar contains an entry for this variant (Variation ID: 37402). Based on the evidence outlined above, the variant was classified as likely benign. -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter
Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);Loss of methylation at K45 (P = 0);