Submissions for variant NM_007294.4(BRCA1):c.4181C>T (p.Thr1394Ile)

gnomAD frequency: 0.00001  dbSNP: rs397507226

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164912	SCV000215600	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-24	criteria provided, single submitter	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.
GeneDx	RCV000236566	SCV000294090	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530171	SCV000635952	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164912	SCV000909275	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-13	criteria provided, single submitter	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236566	SCV001470178	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226170	SCV003923023	likely benign	not specified	2024-12-23	criteria provided, single submitter	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.
All of Us Research Program, National Institutes of Health	RCV004802981	SCV004817698	uncertain significance	BRCA1-related cancer predisposition	2024-04-16	criteria provided, single submitter	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.
Sharing Clinical Reports Project (SCRP)	RCV000031154	SCV000053754	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-08-06	no assertion criteria provided	clinical testing