Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP3BP6
The NM_007294.4(BRCA1):c.4181C>T(p.Thr1394Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,609,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1394T) has been classified as Pathogenic.
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
In a mutagenesis_site Reduces in vitro phosphorylation by ATR. (size 0) in uniprot entity BRCA1_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.769
BP6
Variant 17-43090948-G-A is Benign according to our data. Variant chr17-43090948-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37573.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
In the published literature, this variant has been reported in individuals with breast cancer (PMID: 33646313 (2021), 26287763 (2015)). Published functional studies have reported conflicting effects of this variant on BRCA1 protein function (PMID: 34749799 (2021), 34301763 (2021), 28781887 (2016)). The frequency of this variant in the general population, 0.0000066 (1/152182 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Mar 01, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Observed in individuals with breast cancer (PMID: 33646313, 26287763); Published functional studies demonstrate transcriptional activation and cell survival comparable to wildtype, but decreased homology-directed repair activity and increased sensitivity to DNA damaging agents (PMID: 34749799, 28781887, 34301763); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 4300C>T; This variant is associated with the following publications: (PMID: 15343273, 22737296, 33646313, 34749799, 31853058, 28781887, 34301763, 29884841, 26287763, 32377563, 35665744) -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.T1394I variant (also known as c.4181C>T), located in coding exon 10 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4181. The threonine at codon 1394 is replaced by isoleucine, an amino acid with similar properties. This alteration has been identified in individuals diagnosed with breast cancer (Pal T et al. Cancer. 2015 Dec 1;121(23):4173-80; George SHL et al. JAMA Netw Open, 2021 03;4:e210307). In one study, this variant was classified as functionally 'likely not pathogenic' by using a Bayesian hierarchical model (VarCall) which incorporates direct transcriptional activation function measurements of BRCA1 variants to predict pathogenicity (Woods NT et al. Genomic Med. 2016 Mar 1:16001). This variant also performed similar to wildtype in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet. Med., 2019 01;21:71-80). This alteration is also known as 4300C>T in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Apr 02, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces threonine with isoleucine at codon 1394 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have reported that this variant does not impact BRCA1 function in a homology-directed repair and transcriptional activation assays and the survival of NHEJ DNA repair-deficient haploid human cells (PMID: 28781887, 29884841, 34749799). However, another study has implicated Thr1394 in the regulation of BRCA1 function by ATM/ATR in promoting homology-directed DNA repair and G 2-M checkpoint maintenance (PMID: 34301763). This variant has been reported in at least one individual affected with breast cancer before age 50 (PMID: 26287763). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
BRCA1-related cancer predisposition Uncertain:1
Apr 16, 2024
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces threonine with isoleucine at codon 1394 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in a homology-directed repair assay and transcriptional activation assays (PMID: 28781887, 29884841). However, another study has implicated Thr1394 in the regulation of BRCA1 function by ATM/ATR in promoting homology-directed DNA repair and G 2-M checkpoint maintenance (PMID: 34301763). This variant has been reported in at least one individual affected with breast cancer before age 50 (PMID: 26287763). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not specified Benign:1
Dec 23, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.4181C>T (p.Thr1394Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 244234 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4181C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Pal_2015, George_2021) without strong evidence for causality. Several publications report experimental evidence evaluating an impact on protein function: these studies demonstrated that the variant had similar function as wildtype (Billaud_2021, Woods_2016, Hart_2019, Foo_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34749799, 34301763, 33646313, 29884841, 26287763, 28781887). ClinVar contains an entry for this variant (Variation ID: 37573). Based on the evidence outlined above, the variant was classified as likely benign. -
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1
Aug 06, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Benign:1
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter