Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_007294.4(BRCA1):c.1459G>T(p.Val487Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,120 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V487A) 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 -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.20429519).
BP6
Variant 17-43094072-C-A is Benign according to our data. Variant chr17-43094072-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37414.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=6}.
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 04, 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. -
Uncertain significance, criteria provided, single submitter
curation
Sema4, Sema4
Nov 19, 2021
- -
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jul 05, 2017
- -
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:2Benign:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Nov 22, 2022
Identified in an individual with advanced cancer (Mandelker et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 1578G>T; This variant is associated with the following publications: (PMID: 31853058, 29884841, 32377563, 28873162, 15343273, Villela2022[preprint]) -
Uncertain significance, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Jan 09, 2018
- -
Likely benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Oct 11, 2022
- -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Feb 12, 2016
- -
Likely benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Sep 03, 2010
- -
not specified Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Oct 10, 2022
Variant summary: BRCA1 c.1459G>T (p.Val487Phe) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251284 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. This frequency is only slightly lower than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00062 vs 0.001), suggesting that the variant could be a benign polymorphism found primarily in populations of African origin. This variant is also reported in the FLOSSIES database among African American individuals over age 70 with no history of cancer. To our knowledge, no occurrence of c.1459G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=4; likely benign, n=4). Based on the emerging consensus among peers and the evidence outlined above, the variant was classified as likely benign. -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter