Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBP6_Very_Strong
The NM_007294.4(BRCA1):c.5402G>A(p.Gly1801Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1801A) 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]
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 17 uncertain in NM_007294.4
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.04499677).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43049125-C-T is Benign according to our data. Variant chr17-43049125-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 142834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Jul 26, 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. -
Benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jun 06, 2016
- -
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Jan 27, 2021
- -
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1Other:1
Benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Jan 03, 2024
- -
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
- -
not specified Benign:1
Benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jan 30, 2021
Variant summary: BRCA1 c.5402G>A (p.Gly1801Asp) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5402G>A has been reported in the literature in individuals affected with breast and ovarian cancer (e.g. Mehta_2018, Manie_2016) and as an unclassified variant in at-least two relatives of patients with early-onset breast cancer (Juwle_2012) without strong evidence of causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least two publications report experimental evidence evaluating an impact on homology directed repair (HDR) activity (example, Lu_2015, Findlay_2018). Both studies no impact of this variant on HDR activity. 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 benign/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
Mar 02, 2020
This variant is associated with the following publications: (PMID: 24265153, 26689913, 22752604, 30209399, 30555256, 33087888) -
Hereditary breast ovarian cancer syndrome Benign:1