Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBP6_Very_Strong
The NM_007294.4(BRCA1):c.4691T>C(p.Leu1564Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,614,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1564V) 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 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=0.047209352).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43071223-A-G is Benign according to our data. Variant chr17-43071223-A-G is described in ClinVar as [Benign]. Clinvar id is 55262.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43071223-A-G is described in Lovd as [Benign].
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:4
Benign, criteria provided, single submitter
clinical testing
Mendelics
May 28, 2019
- -
Benign, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
May 29, 2002
- -
Likely benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Jan 08, 2024
- -
Benign, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Aug 10, 2015
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000102 -
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
May 05, 2015
- -
Likely benign, no assertion criteria provided
clinical testing
True Health Diagnostics
Jan 03, 2018
- -
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Nov 11, 2020
- -
Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 18, 2014
This alteration is classified as 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 provided Benign:3
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Jul 11, 2017
- -
Benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Mar 17, 2016
Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a medium size and hydrophobic Leucine (L) with a medium size and hydrophobic Proline (P). 3/4 in silico tools predict the variant to be neutral. It was observed predominantly in the African subcohorts of the ExAC project at an allele frequency of 0.13% which slightly exceeds the maximal expected allele frequency of a disease causing BRCA1 allele (0.1%). It was reported in several HBOC spectrum patients however without strong evidence for pathogenicity. The variant was observed to co-occur with pathogenic/possibly pathogenic BRCA1 and BRCA2 variants such as BRCA1 p.C64Y; p.Lys1290Ter, p.Val738fs, c.824ins10 and BRCA2 p.Lys1872_Ile1874fs indicating neutrality. A benign impact is also supported by computational analysis that integrated multiple forms of genetic evidence for the variant of interest (Lindor_2012). Carvalho_2007 showed decreased transcriptional activity in yeast and mammalian cells; however, Hayes_2000 showed transcription activation of the variant is comparable to wild-type BRCA1 in yeast. In addition, multiple literature and reputable databases/clinical laboratories classify this variant as likely benign or benign. Considering all evidence, the variant was classified as Benign. -
Benign, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Aug 15, 2021
- -
not specified Benign:2Other:1
not provided, no classification provided
reference population
ITMI
Sep 19, 2013
- -
Likely benign, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Jun 11, 2019
- -
Benign, criteria provided, single submitter
clinical testing
GeneDx
Jun 27, 2017
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Hereditary breast ovarian cancer syndrome Benign:2
Benign, criteria provided, single submitter
clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Nov 15, 2022
- -
Benign, criteria provided, single submitter
clinical testing
Invitae
Jan 31, 2024
- -
Breast neoplasm Benign:1
Likely benign, no assertion criteria provided
research
CSER _CC_NCGL, University of Washington
Jun 01, 2014
- -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1