rs397507226
Variant summary
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.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457002Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 724298
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2024 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 13, 2023 | 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 13, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 2023 | 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. - |
BRCA1-related cancer predisposition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 16, 2024 | 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
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 24, 2023 | 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). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Aug 06, 2012 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 20, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at