Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4BP6_Very_Strong
The NM_007294.4(BRCA1):c.2884G>A(p.Glu962Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. E962G) 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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Benign. The variant received -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.267224).
BP6
Variant 17-43092647-C-T is Benign according to our data. Variant chr17-43092647-C-T is described in ClinVar as [Benign]. Clinvar id is 54709.Status of the report is reviewed_by_expert_panel, 3 stars.
This variant is denoted BRCA1 c.2884G>A at the cDNA level, p.Glu962Lys (E962K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant, also known as BRCA1 3003G>A using alternate nomenclature, has been observed in a woman with a history of unilateral breast cancer (Borg 2010). An in vitro-based homology-directed repair (HDR) assay showed this variant to exhibit HDR activity comparable to wildtype (Lu 2015). BRCA1 Glu962Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA and RAD51 binding domains (Chen 1998, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Glu962Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Nov 11, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Oct 23, 2020
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:1Benign:2
Jun 18, 2019
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance:Benign
Review Status:reviewed by expert panel
Collection Method:curation
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 = 0.000971 -
Feb 20, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Mar 02, 2020
BRCAlab, Lund University
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Hereditary cancer-predisposing syndromeBenign:2
Feb 03, 2021
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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. -
Mar 30, 2016
Color Diagnostics, LLC DBA Color Health
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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not specifiedUncertain:1
Dec 28, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: The BRCA1 c.2884G>A (p.Glu962Lys) variant involves the alteration of a non-conserved nucleotide, that results in the substitution of a glutamine amino acid for lysine in the DNA binding domain of the BRCA1 protein (Lu 2015). Since a lysine amino acid residue is found in multiple mammalian species at this position, this suggests that the variant of interest might not adversely affect protein function. 3/5 in silico tools predict a benign outcome for this variant. Moreover, in a functional study the variant protein was found to have a similar homology-directed repair (HDR) activity to the wild type protein (Lu 2015). This variant was found in 4/277044 control chromosomes at a frequency of 0.0000144, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). Though the variant has been reported in HBOC patients (Judkins 2005, Borg 2010), no convincing evidence was provided for causality. This variant has been reported in five patients in the UMD database, however a pathogenic BRCA2 variant (c.145G>T (p.Glu49X)) was also present in one of the patients, suggesting that the variant of interest was not the primary cause of disease in this patient. Though multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, considering all the available evidence, this variant is classified as VUS possibly benign. -