Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_007294.4(BRCA1):c.2963C>T(p.Ser988Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S988S) has been classified 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 -1 ACMG points.
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43092568-G-A is Benign according to our data. Variant chr17-43092568-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37494.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1}.
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:3
Likely benign, no assertion criteria provided
clinical testing
BRCAlab, Lund University
Mar 02, 2020
- -
Likely benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
May 30, 2023
- -
Benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Feb 01, 2012
- -
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 16, 2020
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. -
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Mar 12, 2018
- -
Likely benign, criteria provided, single submitter
curation
University of Washington Department of Laboratory Medicine, University of Washington
Mar 23, 2023
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Mar 05, 2021
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25722345, 22476429, 27767231, 31131967, 32546644, 30212499) -
Uncertain significance, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Mar 18, 2015
- -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter