Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6
The NM_007294.4(BRCA1):c.1258G>T(p.Asp420Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,062 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. D420G) 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 -2 ACMG points.
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=0.3913424).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43094273-C-A is Benign according to our data. Variant chr17-43094273-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54178.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, Uncertain_significance=1}. Variant chr17-43094273-C-A is described in Lovd as [Benign].
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Mar 13, 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. -
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). -
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jul 21, 2017
- -
not provided Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Nov 01, 2022
- -
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Oct 12, 2018
This variant is associated with the following publications: (PMID: 16518693, 22753008, 17924331, 21990134, 29161300, 33087888) -
Hereditary breast ovarian cancer syndrome Benign:2
Benign, criteria provided, single submitter
clinical testing
Mendelics
Aug 22, 2023
- -
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Dec 13, 2023
- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Dec 31, 2022
Variant summary: BRCA1 c.1258G>T (p.Asp420Tyr) 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 2.4e-05 in 250814 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1258G>T has been reported in the literature as a VUS in individuals affected with Breast and/or Ovarian Cancer (example, Alemar_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models have predicted a neutral/benign (not pathogenic) IARC class 1 outcome for this variant (example, Lindor_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 (LB, n=4; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1
Uncertain significance, no assertion criteria provided