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.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.4181C>T (p.Thr1394Ile)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(8)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Uncertain significance(5); Likely benign(2)
Uncertain significance(5); Likely benign(2)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.4181C>T (p.Thr1394Ile)
Variation ID: 37573 Accession: VCV000037573.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43090948 (GRCh38) [ NCBI UCSC ] 17: 41242965 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 27, 2014 Sep 29, 2024 Mar 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.4181C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Thr1394Ile missense NM_001407571.1:c.3968C>T NP_001394500.1:p.Thr1323Ile missense NM_001407581.1:c.4181C>T NP_001394510.1:p.Thr1394Ile missense NM_001407582.1:c.4181C>T NP_001394511.1:p.Thr1394Ile missense NM_001407583.1:c.4181C>T NP_001394512.1:p.Thr1394Ile missense NM_001407585.1:c.4181C>T NP_001394514.1:p.Thr1394Ile missense NM_001407587.1:c.4178C>T NP_001394516.1:p.Thr1393Ile missense NM_001407590.1:c.4178C>T NP_001394519.1:p.Thr1393Ile missense NM_001407591.1:c.4178C>T NP_001394520.1:p.Thr1393Ile missense NM_001407593.1:c.4181C>T NP_001394522.1:p.Thr1394Ile missense NM_001407594.1:c.4181C>T NP_001394523.1:p.Thr1394Ile missense NM_001407596.1:c.4181C>T NP_001394525.1:p.Thr1394Ile missense NM_001407597.1:c.4181C>T NP_001394526.1:p.Thr1394Ile missense NM_001407598.1:c.4181C>T NP_001394527.1:p.Thr1394Ile missense NM_001407602.1:c.4181C>T NP_001394531.1:p.Thr1394Ile missense NM_001407603.1:c.4181C>T NP_001394532.1:p.Thr1394Ile missense NM_001407605.1:c.4181C>T NP_001394534.1:p.Thr1394Ile missense NM_001407610.1:c.4178C>T NP_001394539.1:p.Thr1393Ile missense NM_001407611.1:c.4178C>T NP_001394540.1:p.Thr1393Ile missense NM_001407612.1:c.4178C>T NP_001394541.1:p.Thr1393Ile missense NM_001407613.1:c.4178C>T NP_001394542.1:p.Thr1393Ile missense NM_001407614.1:c.4178C>T NP_001394543.1:p.Thr1393Ile missense NM_001407615.1:c.4178C>T NP_001394544.1:p.Thr1393Ile missense NM_001407616.1:c.4181C>T NP_001394545.1:p.Thr1394Ile missense NM_001407617.1:c.4181C>T NP_001394546.1:p.Thr1394Ile missense NM_001407618.1:c.4181C>T NP_001394547.1:p.Thr1394Ile missense NM_001407619.1:c.4181C>T NP_001394548.1:p.Thr1394Ile missense NM_001407620.1:c.4181C>T NP_001394549.1:p.Thr1394Ile missense NM_001407621.1:c.4181C>T NP_001394550.1:p.Thr1394Ile missense NM_001407622.1:c.4181C>T NP_001394551.1:p.Thr1394Ile missense NM_001407623.1:c.4181C>T NP_001394552.1:p.Thr1394Ile missense NM_001407624.1:c.4181C>T NP_001394553.1:p.Thr1394Ile missense NM_001407625.1:c.4181C>T NP_001394554.1:p.Thr1394Ile missense NM_001407626.1:c.4181C>T NP_001394555.1:p.Thr1394Ile missense NM_001407627.1:c.4178C>T NP_001394556.1:p.Thr1393Ile missense NM_001407628.1:c.4178C>T NP_001394557.1:p.Thr1393Ile missense NM_001407629.1:c.4178C>T NP_001394558.1:p.Thr1393Ile missense NM_001407630.1:c.4178C>T NP_001394559.1:p.Thr1393Ile missense NM_001407631.1:c.4178C>T NP_001394560.1:p.Thr1393Ile missense NM_001407632.1:c.4178C>T NP_001394561.1:p.Thr1393Ile missense NM_001407633.1:c.4178C>T NP_001394562.1:p.Thr1393Ile missense NM_001407634.1:c.4178C>T NP_001394563.1:p.Thr1393Ile missense NM_001407635.1:c.4178C>T NP_001394564.1:p.Thr1393Ile missense NM_001407636.1:c.4178C>T NP_001394565.1:p.Thr1393Ile missense NM_001407637.1:c.4178C>T NP_001394566.1:p.Thr1393Ile missense NM_001407638.1:c.4178C>T NP_001394567.1:p.Thr1393Ile missense NM_001407639.1:c.4181C>T NP_001394568.1:p.Thr1394Ile missense NM_001407640.1:c.4181C>T NP_001394569.1:p.Thr1394Ile missense NM_001407641.1:c.4181C>T NP_001394570.1:p.Thr1394Ile missense NM_001407642.1:c.4181C>T NP_001394571.1:p.Thr1394Ile missense NM_001407644.1:c.4178C>T NP_001394573.1:p.Thr1393Ile missense NM_001407645.1:c.4178C>T NP_001394574.1:p.Thr1393Ile missense NM_001407646.1:c.4172C>T NP_001394575.1:p.Thr1391Ile missense NM_001407647.1:c.4172C>T NP_001394576.1:p.Thr1391Ile missense NM_001407648.1:c.4058C>T NP_001394577.1:p.Thr1353Ile missense NM_001407649.1:c.4055C>T NP_001394578.1:p.Thr1352Ile missense NM_001407652.1:c.4181C>T NP_001394581.1:p.Thr1394Ile missense NM_001407653.1:c.4103C>T NP_001394582.1:p.Thr1368Ile missense NM_001407654.1:c.4103C>T NP_001394583.1:p.Thr1368Ile missense NM_001407655.1:c.4103C>T NP_001394584.1:p.Thr1368Ile missense NM_001407656.1:c.4103C>T NP_001394585.1:p.Thr1368Ile missense NM_001407657.1:c.4103C>T NP_001394586.1:p.Thr1368Ile missense NM_001407658.1:c.4103C>T NP_001394587.1:p.Thr1368Ile missense NM_001407659.1:c.4100C>T NP_001394588.1:p.Thr1367Ile missense NM_001407660.1:c.4100C>T NP_001394589.1:p.Thr1367Ile missense NM_001407661.1:c.4100C>T NP_001394590.1:p.Thr1367Ile missense NM_001407662.1:c.4100C>T NP_001394591.1:p.Thr1367Ile missense NM_001407663.1:c.4103C>T NP_001394592.1:p.Thr1368Ile missense NM_001407664.1:c.4058C>T NP_001394593.1:p.Thr1353Ile missense NM_001407665.1:c.4058C>T NP_001394594.1:p.Thr1353Ile missense NM_001407666.1:c.4058C>T NP_001394595.1:p.Thr1353Ile missense NM_001407667.1:c.4058C>T NP_001394596.1:p.Thr1353Ile missense NM_001407668.1:c.4058C>T NP_001394597.1:p.Thr1353Ile missense NM_001407669.1:c.4058C>T NP_001394598.1:p.Thr1353Ile missense NM_001407670.1:c.4055C>T NP_001394599.1:p.Thr1352Ile missense NM_001407671.1:c.4055C>T NP_001394600.1:p.Thr1352Ile missense NM_001407672.1:c.4055C>T NP_001394601.1:p.Thr1352Ile missense NM_001407673.1:c.4055C>T NP_001394602.1:p.Thr1352Ile missense NM_001407674.1:c.4058C>T NP_001394603.1:p.Thr1353Ile missense NM_001407675.1:c.4058C>T NP_001394604.1:p.Thr1353Ile missense NM_001407676.1:c.4058C>T NP_001394605.1:p.Thr1353Ile missense NM_001407677.1:c.4058C>T NP_001394606.1:p.Thr1353Ile missense NM_001407678.1:c.4058C>T NP_001394607.1:p.Thr1353Ile missense NM_001407679.1:c.4058C>T NP_001394608.1:p.Thr1353Ile missense NM_001407680.1:c.4058C>T NP_001394609.1:p.Thr1353Ile missense NM_001407681.1:c.4058C>T NP_001394610.1:p.Thr1353Ile missense NM_001407682.1:c.4058C>T NP_001394611.1:p.Thr1353Ile missense NM_001407683.1:c.4058C>T NP_001394612.1:p.Thr1353Ile missense NM_001407684.1:c.4181C>T NP_001394613.1:p.Thr1394Ile missense NM_001407685.1:c.4055C>T NP_001394614.1:p.Thr1352Ile missense NM_001407686.1:c.4055C>T NP_001394615.1:p.Thr1352Ile missense NM_001407687.1:c.4055C>T NP_001394616.1:p.Thr1352Ile missense NM_001407688.1:c.4055C>T NP_001394617.1:p.Thr1352Ile missense NM_001407689.1:c.4055C>T NP_001394618.1:p.Thr1352Ile missense NM_001407690.1:c.4055C>T NP_001394619.1:p.Thr1352Ile missense NM_001407691.1:c.4055C>T NP_001394620.1:p.Thr1352Ile missense NM_001407692.1:c.4040C>T NP_001394621.1:p.Thr1347Ile missense NM_001407694.1:c.4040C>T NP_001394623.1:p.Thr1347Ile missense NM_001407695.1:c.4040C>T NP_001394624.1:p.Thr1347Ile missense NM_001407696.1:c.4040C>T NP_001394625.1:p.Thr1347Ile missense NM_001407697.1:c.4040C>T NP_001394626.1:p.Thr1347Ile missense NM_001407698.1:c.4040C>T NP_001394627.1:p.Thr1347Ile missense NM_001407724.1:c.4040C>T NP_001394653.1:p.Thr1347Ile missense NM_001407725.1:c.4040C>T NP_001394654.1:p.Thr1347Ile missense NM_001407726.1:c.4040C>T NP_001394655.1:p.Thr1347Ile missense NM_001407727.1:c.4040C>T NP_001394656.1:p.Thr1347Ile missense NM_001407728.1:c.4040C>T NP_001394657.1:p.Thr1347Ile missense NM_001407729.1:c.4040C>T NP_001394658.1:p.Thr1347Ile missense NM_001407730.1:c.4040C>T NP_001394659.1:p.Thr1347Ile missense NM_001407731.1:c.4040C>T NP_001394660.1:p.Thr1347Ile missense NM_001407732.1:c.4040C>T NP_001394661.1:p.Thr1347Ile missense NM_001407733.1:c.4040C>T NP_001394662.1:p.Thr1347Ile missense NM_001407734.1:c.4040C>T NP_001394663.1:p.Thr1347Ile missense NM_001407735.1:c.4040C>T NP_001394664.1:p.Thr1347Ile missense NM_001407736.1:c.4040C>T NP_001394665.1:p.Thr1347Ile missense NM_001407737.1:c.4040C>T NP_001394666.1:p.Thr1347Ile missense NM_001407738.1:c.4040C>T NP_001394667.1:p.Thr1347Ile missense NM_001407739.1:c.4040C>T NP_001394668.1:p.Thr1347Ile missense NM_001407740.1:c.4037C>T NP_001394669.1:p.Thr1346Ile missense NM_001407741.1:c.4037C>T NP_001394670.1:p.Thr1346Ile missense NM_001407742.1:c.4037C>T NP_001394671.1:p.Thr1346Ile missense NM_001407743.1:c.4037C>T NP_001394672.1:p.Thr1346Ile missense NM_001407744.1:c.4037C>T NP_001394673.1:p.Thr1346Ile missense NM_001407745.1:c.4037C>T NP_001394674.1:p.Thr1346Ile missense NM_001407746.1:c.4037C>T NP_001394675.1:p.Thr1346Ile missense NM_001407747.1:c.4037C>T NP_001394676.1:p.Thr1346Ile missense NM_001407748.1:c.4037C>T NP_001394677.1:p.Thr1346Ile missense NM_001407749.1:c.4037C>T NP_001394678.1:p.Thr1346Ile missense NM_001407750.1:c.4040C>T NP_001394679.1:p.Thr1347Ile missense NM_001407751.1:c.4040C>T NP_001394680.1:p.Thr1347Ile missense NM_001407752.1:c.4040C>T NP_001394681.1:p.Thr1347Ile missense NM_001407838.1:c.4037C>T NP_001394767.1:p.Thr1346Ile missense NM_001407839.1:c.4037C>T NP_001394768.1:p.Thr1346Ile missense NM_001407841.1:c.4037C>T NP_001394770.1:p.Thr1346Ile missense NM_001407842.1:c.4037C>T NP_001394771.1:p.Thr1346Ile missense NM_001407843.1:c.4037C>T NP_001394772.1:p.Thr1346Ile missense NM_001407844.1:c.4037C>T NP_001394773.1:p.Thr1346Ile missense NM_001407845.1:c.4037C>T NP_001394774.1:p.Thr1346Ile missense NM_001407846.1:c.4037C>T NP_001394775.1:p.Thr1346Ile missense NM_001407847.1:c.4037C>T NP_001394776.1:p.Thr1346Ile missense NM_001407848.1:c.4037C>T NP_001394777.1:p.Thr1346Ile missense NM_001407849.1:c.4037C>T NP_001394778.1:p.Thr1346Ile missense NM_001407850.1:c.4040C>T NP_001394779.1:p.Thr1347Ile missense NM_001407851.1:c.4040C>T NP_001394780.1:p.Thr1347Ile missense NM_001407852.1:c.4040C>T NP_001394781.1:p.Thr1347Ile missense NM_001407853.1:c.3968C>T NP_001394782.1:p.Thr1323Ile missense NM_001407854.1:c.4181C>T NP_001394783.1:p.Thr1394Ile missense NM_001407858.1:c.4181C>T NP_001394787.1:p.Thr1394Ile missense NM_001407859.1:c.4181C>T NP_001394788.1:p.Thr1394Ile missense NM_001407860.1:c.4178C>T NP_001394789.1:p.Thr1393Ile missense NM_001407861.1:c.4178C>T NP_001394790.1:p.Thr1393Ile missense NM_001407862.1:c.3980C>T NP_001394791.1:p.Thr1327Ile missense NM_001407863.1:c.4058C>T NP_001394792.1:p.Thr1353Ile missense NM_001407874.1:c.3977C>T NP_001394803.1:p.Thr1326Ile missense NM_001407875.1:c.3977C>T NP_001394804.1:p.Thr1326Ile missense NM_001407879.1:c.3971C>T NP_001394808.1:p.Thr1324Ile missense NM_001407881.1:c.3971C>T NP_001394810.1:p.Thr1324Ile missense NM_001407882.1:c.3971C>T NP_001394811.1:p.Thr1324Ile missense NM_001407884.1:c.3971C>T NP_001394813.1:p.Thr1324Ile missense NM_001407885.1:c.3971C>T NP_001394814.1:p.Thr1324Ile missense NM_001407886.1:c.3971C>T NP_001394815.1:p.Thr1324Ile missense NM_001407887.1:c.3971C>T NP_001394816.1:p.Thr1324Ile missense NM_001407889.1:c.3971C>T NP_001394818.1:p.Thr1324Ile missense NM_001407894.1:c.3968C>T NP_001394823.1:p.Thr1323Ile missense NM_001407895.1:c.3968C>T NP_001394824.1:p.Thr1323Ile missense NM_001407896.1:c.3968C>T NP_001394825.1:p.Thr1323Ile missense NM_001407897.1:c.3968C>T NP_001394826.1:p.Thr1323Ile missense NM_001407898.1:c.3968C>T NP_001394827.1:p.Thr1323Ile missense NM_001407899.1:c.3968C>T NP_001394828.1:p.Thr1323Ile missense NM_001407900.1:c.3971C>T NP_001394829.1:p.Thr1324Ile missense NM_001407902.1:c.3971C>T NP_001394831.1:p.Thr1324Ile missense NM_001407904.1:c.3971C>T NP_001394833.1:p.Thr1324Ile missense NM_001407906.1:c.3971C>T NP_001394835.1:p.Thr1324Ile missense NM_001407907.1:c.3971C>T NP_001394836.1:p.Thr1324Ile missense NM_001407908.1:c.3971C>T NP_001394837.1:p.Thr1324Ile missense NM_001407909.1:c.3971C>T NP_001394838.1:p.Thr1324Ile missense NM_001407910.1:c.3971C>T NP_001394839.1:p.Thr1324Ile missense NM_001407915.1:c.3968C>T NP_001394844.1:p.Thr1323Ile missense NM_001407916.1:c.3968C>T NP_001394845.1:p.Thr1323Ile missense NM_001407917.1:c.3968C>T NP_001394846.1:p.Thr1323Ile missense NM_001407918.1:c.3968C>T NP_001394847.1:p.Thr1323Ile missense NM_001407919.1:c.4058C>T NP_001394848.1:p.Thr1353Ile missense NM_001407920.1:c.3917C>T NP_001394849.1:p.Thr1306Ile missense NM_001407921.1:c.3917C>T NP_001394850.1:p.Thr1306Ile missense NM_001407922.1:c.3917C>T NP_001394851.1:p.Thr1306Ile missense NM_001407923.1:c.3917C>T NP_001394852.1:p.Thr1306Ile missense NM_001407924.1:c.3917C>T NP_001394853.1:p.Thr1306Ile missense NM_001407925.1:c.3917C>T NP_001394854.1:p.Thr1306Ile missense NM_001407926.1:c.3917C>T NP_001394855.1:p.Thr1306Ile missense NM_001407927.1:c.3917C>T NP_001394856.1:p.Thr1306Ile missense NM_001407928.1:c.3917C>T NP_001394857.1:p.Thr1306Ile missense NM_001407929.1:c.3917C>T NP_001394858.1:p.Thr1306Ile missense NM_001407930.1:c.3914C>T NP_001394859.1:p.Thr1305Ile missense NM_001407931.1:c.3914C>T NP_001394860.1:p.Thr1305Ile missense NM_001407932.1:c.3914C>T NP_001394861.1:p.Thr1305Ile missense NM_001407933.1:c.3917C>T NP_001394862.1:p.Thr1306Ile missense NM_001407934.1:c.3914C>T NP_001394863.1:p.Thr1305Ile missense NM_001407935.1:c.3917C>T NP_001394864.1:p.Thr1306Ile missense NM_001407936.1:c.3914C>T NP_001394865.1:p.Thr1305Ile missense NM_001407937.1:c.4058C>T NP_001394866.1:p.Thr1353Ile missense NM_001407938.1:c.4058C>T NP_001394867.1:p.Thr1353Ile missense NM_001407939.1:c.4058C>T NP_001394868.1:p.Thr1353Ile missense NM_001407940.1:c.4055C>T NP_001394869.1:p.Thr1352Ile missense NM_001407941.1:c.4055C>T NP_001394870.1:p.Thr1352Ile missense NM_001407942.1:c.4040C>T NP_001394871.1:p.Thr1347Ile missense NM_001407943.1:c.4037C>T NP_001394872.1:p.Thr1346Ile missense NM_001407944.1:c.4040C>T NP_001394873.1:p.Thr1347Ile missense NM_001407945.1:c.4040C>T NP_001394874.1:p.Thr1347Ile missense NM_001407946.1:c.3848C>T NP_001394875.1:p.Thr1283Ile missense NM_001407947.1:c.3848C>T NP_001394876.1:p.Thr1283Ile missense NM_001407948.1:c.3848C>T NP_001394877.1:p.Thr1283Ile missense NM_001407949.1:c.3848C>T NP_001394878.1:p.Thr1283Ile missense NM_001407950.1:c.3848C>T NP_001394879.1:p.Thr1283Ile missense NM_001407951.1:c.3848C>T NP_001394880.1:p.Thr1283Ile missense NM_001407952.1:c.3848C>T NP_001394881.1:p.Thr1283Ile missense NM_001407953.1:c.3848C>T NP_001394882.1:p.Thr1283Ile missense NM_001407954.1:c.3845C>T NP_001394883.1:p.Thr1282Ile missense NM_001407955.1:c.3845C>T NP_001394884.1:p.Thr1282Ile missense NM_001407956.1:c.3845C>T NP_001394885.1:p.Thr1282Ile missense NM_001407957.1:c.3848C>T NP_001394886.1:p.Thr1283Ile missense NM_001407958.1:c.3845C>T NP_001394887.1:p.Thr1282Ile missense NM_001407959.1:c.3800C>T NP_001394888.1:p.Thr1267Ile missense NM_001407960.1:c.3800C>T NP_001394889.1:p.Thr1267Ile missense NM_001407962.1:c.3797C>T NP_001394891.1:p.Thr1266Ile missense NM_001407963.1:c.3800C>T NP_001394892.1:p.Thr1267Ile missense NM_001407964.1:c.4037C>T NP_001394893.1:p.Thr1346Ile missense NM_001407965.1:c.3677C>T NP_001394894.1:p.Thr1226Ile missense NM_001407966.1:c.3293C>T NP_001394895.1:p.Thr1098Ile missense NM_001407967.1:c.3293C>T NP_001394896.1:p.Thr1098Ile missense NM_001407968.1:c.1577C>T NP_001394897.1:p.Thr526Ile missense NM_001407969.1:c.1577C>T NP_001394898.1:p.Thr526Ile missense NM_001407970.1:c.872C>T NP_001394899.1:p.Thr291Ile missense NM_001407971.1:c.872C>T NP_001394900.1:p.Thr291Ile missense NM_001407972.1:c.869C>T NP_001394901.1:p.Thr290Ile missense NM_001407973.1:c.872C>T NP_001394902.1:p.Thr291Ile missense NM_001407974.1:c.872C>T NP_001394903.1:p.Thr291Ile missense NM_001407975.1:c.872C>T NP_001394904.1:p.Thr291Ile missense NM_001407976.1:c.872C>T NP_001394905.1:p.Thr291Ile missense NM_001407977.1:c.872C>T NP_001394906.1:p.Thr291Ile missense NM_001407978.1:c.872C>T NP_001394907.1:p.Thr291Ile missense NM_001407979.1:c.872C>T NP_001394908.1:p.Thr291Ile missense NM_001407980.1:c.872C>T NP_001394909.1:p.Thr291Ile missense NM_001407981.1:c.872C>T NP_001394910.1:p.Thr291Ile missense NM_001407982.1:c.872C>T NP_001394911.1:p.Thr291Ile missense NM_001407983.1:c.872C>T NP_001394912.1:p.Thr291Ile missense NM_001407984.1:c.869C>T NP_001394913.1:p.Thr290Ile missense NM_001407985.1:c.869C>T NP_001394914.1:p.Thr290Ile missense NM_001407986.1:c.869C>T NP_001394915.1:p.Thr290Ile missense NM_001407990.1:c.872C>T NP_001394919.1:p.Thr291Ile missense NM_001407991.1:c.869C>T NP_001394920.1:p.Thr290Ile missense NM_001407992.1:c.869C>T NP_001394921.1:p.Thr290Ile missense NM_001407993.1:c.872C>T NP_001394922.1:p.Thr291Ile missense NM_001408392.1:c.869C>T NP_001395321.1:p.Thr290Ile missense NM_001408396.1:c.869C>T NP_001395325.1:p.Thr290Ile missense NM_001408397.1:c.869C>T NP_001395326.1:p.Thr290Ile missense NM_001408398.1:c.869C>T NP_001395327.1:p.Thr290Ile missense NM_001408399.1:c.869C>T NP_001395328.1:p.Thr290Ile missense NM_001408400.1:c.869C>T NP_001395329.1:p.Thr290Ile missense NM_001408401.1:c.869C>T NP_001395330.1:p.Thr290Ile missense NM_001408402.1:c.869C>T NP_001395331.1:p.Thr290Ile missense NM_001408403.1:c.872C>T NP_001395332.1:p.Thr291Ile missense NM_001408404.1:c.872C>T NP_001395333.1:p.Thr291Ile missense NM_001408406.1:c.866C>T NP_001395335.1:p.Thr289Ile missense NM_001408407.1:c.869C>T NP_001395336.1:p.Thr290Ile missense NM_001408408.1:c.863C>T NP_001395337.1:p.Thr288Ile missense NM_001408409.1:c.794C>T NP_001395338.1:p.Thr265Ile missense NM_001408410.1:c.731C>T NP_001395339.1:p.Thr244Ile missense NM_001408411.1:c.794C>T NP_001395340.1:p.Thr265Ile missense NM_001408412.1:c.794C>T NP_001395341.1:p.Thr265Ile missense NM_001408413.1:c.791C>T NP_001395342.1:p.Thr264Ile missense NM_001408414.1:c.794C>T NP_001395343.1:p.Thr265Ile missense NM_001408415.1:c.794C>T NP_001395344.1:p.Thr265Ile missense NM_001408416.1:c.791C>T NP_001395345.1:p.Thr264Ile missense NM_001408418.1:c.755C>T NP_001395347.1:p.Thr252Ile missense NM_001408419.1:c.755C>T NP_001395348.1:p.Thr252Ile missense NM_001408420.1:c.755C>T NP_001395349.1:p.Thr252Ile missense NM_001408421.1:c.752C>T NP_001395350.1:p.Thr251Ile missense NM_001408422.1:c.755C>T NP_001395351.1:p.Thr252Ile missense NM_001408423.1:c.755C>T NP_001395352.1:p.Thr252Ile missense NM_001408424.1:c.752C>T NP_001395353.1:p.Thr251Ile missense NM_001408425.1:c.749C>T NP_001395354.1:p.Thr250Ile missense NM_001408426.1:c.749C>T NP_001395355.1:p.Thr250Ile missense NM_001408427.1:c.749C>T NP_001395356.1:p.Thr250Ile missense NM_001408428.1:c.749C>T NP_001395357.1:p.Thr250Ile missense NM_001408429.1:c.749C>T NP_001395358.1:p.Thr250Ile missense NM_001408430.1:c.749C>T NP_001395359.1:p.Thr250Ile missense NM_001408431.1:c.752C>T NP_001395360.1:p.Thr251Ile missense NM_001408432.1:c.746C>T NP_001395361.1:p.Thr249Ile missense NM_001408433.1:c.746C>T NP_001395362.1:p.Thr249Ile missense NM_001408434.1:c.746C>T NP_001395363.1:p.Thr249Ile missense NM_001408435.1:c.746C>T NP_001395364.1:p.Thr249Ile missense NM_001408436.1:c.749C>T NP_001395365.1:p.Thr250Ile missense NM_001408437.1:c.749C>T NP_001395366.1:p.Thr250Ile missense NM_001408438.1:c.749C>T NP_001395367.1:p.Thr250Ile missense NM_001408439.1:c.749C>T NP_001395368.1:p.Thr250Ile missense NM_001408440.1:c.749C>T NP_001395369.1:p.Thr250Ile missense NM_001408441.1:c.749C>T NP_001395370.1:p.Thr250Ile missense NM_001408442.1:c.749C>T NP_001395371.1:p.Thr250Ile missense NM_001408443.1:c.749C>T NP_001395372.1:p.Thr250Ile missense NM_001408444.1:c.749C>T NP_001395373.1:p.Thr250Ile missense NM_001408445.1:c.746C>T NP_001395374.1:p.Thr249Ile missense NM_001408446.1:c.746C>T NP_001395375.1:p.Thr249Ile missense NM_001408447.1:c.746C>T NP_001395376.1:p.Thr249Ile missense NM_001408448.1:c.746C>T NP_001395377.1:p.Thr249Ile missense NM_001408450.1:c.746C>T NP_001395379.1:p.Thr249Ile missense NM_001408451.1:c.737C>T NP_001395380.1:p.Thr246Ile missense NM_001408452.1:c.731C>T NP_001395381.1:p.Thr244Ile missense NM_001408453.1:c.731C>T NP_001395382.1:p.Thr244Ile missense NM_001408454.1:c.731C>T NP_001395383.1:p.Thr244Ile missense NM_001408455.1:c.731C>T NP_001395384.1:p.Thr244Ile missense NM_001408456.1:c.731C>T NP_001395385.1:p.Thr244Ile missense NM_001408457.1:c.731C>T NP_001395386.1:p.Thr244Ile missense NM_001408458.1:c.731C>T NP_001395387.1:p.Thr244Ile missense NM_001408459.1:c.731C>T NP_001395388.1:p.Thr244Ile missense NM_001408460.1:c.731C>T NP_001395389.1:p.Thr244Ile missense NM_001408461.1:c.731C>T NP_001395390.1:p.Thr244Ile missense NM_001408462.1:c.728C>T NP_001395391.1:p.Thr243Ile missense NM_001408463.1:c.728C>T NP_001395392.1:p.Thr243Ile missense NM_001408464.1:c.728C>T NP_001395393.1:p.Thr243Ile missense NM_001408465.1:c.728C>T NP_001395394.1:p.Thr243Ile missense NM_001408466.1:c.731C>T NP_001395395.1:p.Thr244Ile missense NM_001408467.1:c.731C>T NP_001395396.1:p.Thr244Ile missense NM_001408468.1:c.728C>T NP_001395397.1:p.Thr243Ile missense NM_001408469.1:c.731C>T NP_001395398.1:p.Thr244Ile missense NM_001408470.1:c.728C>T NP_001395399.1:p.Thr243Ile missense NM_001408472.1:c.872C>T NP_001395401.1:p.Thr291Ile missense NM_001408473.1:c.869C>T NP_001395402.1:p.Thr290Ile missense NM_001408474.1:c.671C>T NP_001395403.1:p.Thr224Ile missense NM_001408475.1:c.668C>T NP_001395404.1:p.Thr223Ile missense NM_001408476.1:c.671C>T NP_001395405.1:p.Thr224Ile missense NM_001408478.1:c.662C>T NP_001395407.1:p.Thr221Ile missense NM_001408479.1:c.662C>T NP_001395408.1:p.Thr221Ile missense NM_001408480.1:c.662C>T NP_001395409.1:p.Thr221Ile missense NM_001408481.1:c.662C>T NP_001395410.1:p.Thr221Ile missense NM_001408482.1:c.662C>T NP_001395411.1:p.Thr221Ile missense NM_001408483.1:c.662C>T NP_001395412.1:p.Thr221Ile missense NM_001408484.1:c.662C>T NP_001395413.1:p.Thr221Ile missense NM_001408485.1:c.662C>T NP_001395414.1:p.Thr221Ile missense NM_001408489.1:c.662C>T NP_001395418.1:p.Thr221Ile missense NM_001408490.1:c.659C>T NP_001395419.1:p.Thr220Ile missense NM_001408491.1:c.659C>T NP_001395420.1:p.Thr220Ile missense NM_001408492.1:c.662C>T NP_001395421.1:p.Thr221Ile missense NM_001408493.1:c.659C>T NP_001395422.1:p.Thr220Ile missense NM_001408494.1:c.632C>T NP_001395423.1:p.Thr211Ile missense NM_001408495.1:c.629C>T NP_001395424.1:p.Thr210Ile missense NM_001408496.1:c.608C>T NP_001395425.1:p.Thr203Ile missense NM_001408497.1:c.608C>T NP_001395426.1:p.Thr203Ile missense NM_001408498.1:c.608C>T NP_001395427.1:p.Thr203Ile missense NM_001408499.1:c.608C>T NP_001395428.1:p.Thr203Ile missense NM_001408500.1:c.608C>T NP_001395429.1:p.Thr203Ile missense NM_001408501.1:c.608C>T NP_001395430.1:p.Thr203Ile missense NM_001408502.1:c.539C>T NP_001395431.1:p.Thr180Ile missense NM_001408503.1:c.605C>T NP_001395432.1:p.Thr202Ile missense NM_001408504.1:c.605C>T NP_001395433.1:p.Thr202Ile missense NM_001408505.1:c.605C>T NP_001395434.1:p.Thr202Ile missense NM_001408506.1:c.545C>T NP_001395435.1:p.Thr182Ile missense NM_001408507.1:c.545C>T NP_001395436.1:p.Thr182Ile missense NM_001408508.1:c.536C>T NP_001395437.1:p.Thr179Ile missense NM_001408509.1:c.536C>T NP_001395438.1:p.Thr179Ile missense NM_001408510.1:c.491C>T NP_001395439.1:p.Thr164Ile missense NM_001408511.1:c.488C>T NP_001395440.1:p.Thr163Ile missense NM_001408512.1:c.368C>T NP_001395441.1:p.Thr123Ile missense NM_001408513.1:c.662C>T NP_001395442.1:p.Thr221Ile missense NM_001408514.1:c.662C>T NP_001395443.1:p.Thr221Ile missense NM_007297.4:c.4040C>T NP_009228.2:p.Thr1347Ile missense NM_007298.4:c.872C>T NP_009229.2:p.Thr291Ile missense NM_007299.4:c.872C>T NP_009230.2:p.Thr291Ile missense NM_007300.4:c.4181C>T NP_009231.2:p.Thr1394Ile missense NM_007304.2:c.872C>T NP_009235.2:p.Thr291Ile missense NR_027676.2:n.4358C>T non-coding transcript variant NC_000017.11:g.43090948G>A NC_000017.10:g.41242965G>A NG_005905.2:g.127036C>T LRG_292:g.127036C>T LRG_292t1:c.4181C>T LRG_292p1:p.Thr1394Ile - Protein change
- T1394I, T291I, T1347I, T1226I, T1267I, T1324I, T1367I, T1368I, T1393I, T164I, T243I, T249I, T265I, T288I, T1266I, T1326I, T163I, T179I, T180I, T202I, T223I, T246I, T252I, T1098I, T1282I, T1283I, T1327I, T1352I, T1391I, T203I, T210I, T211I, T220I, T221I, T244I, T123I, T1305I, T1306I, T1323I, T1346I, T1353I, T182I, T224I, T250I, T251I, T264I, T289I, T290I, T526I
- Other names
-
4300C>T
- Canonical SPDI
- NC_000017.11:43090947:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13044 | 14850 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, single submitter
|
Aug 28, 2023 | RCV000031154.7 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 24, 2023 | RCV000164912.12 | |
| Likely benign (1) |
criteria provided, single submitter
|
Sep 20, 2023 | RCV000530171.13 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000236566.9 | |
| Likely benign (1) |
criteria provided, single submitter
|
Mar 24, 2023 | RCV003226170.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Oct 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000215600.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Likely benign
(Mar 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003923023.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
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 … (more)
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. (less)
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Likely benign
(Sep 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000635952.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
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Uncertain significance
(Jun 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470178.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000294090.14
First in ClinVar: Jul 24, 2016 Last updated: Sep 29, 2024 |
Comment:
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 … (more)
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) (less)
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Uncertain significance
(Sep 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000909275.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Uncertain Significance
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004817698.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Likely benign
(Aug 06, 2012)
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no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000053754.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
|
Comment:
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Functional pre-therapeutic evaluation by genome editing of variants of uncertain significance of essential tumor suppressor genes. | Billaud A | Genome medicine | 2021 | PMID: 34749799 |
| ATR/ATM-Mediated Phosphorylation of BRCA1 T1394 Promotes Homologous Recombinational Repair and G(2)-M Checkpoint Maintenance. | Foo TK | Cancer research | 2021 | PMID: 34301763 |
| Gene Sequencing for Pathogenic Variants Among Adults With Breast and Ovarian Cancer in the Caribbean. | George SHL | JAMA network open | 2021 | PMID: 33646313 |
| Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. | Hart SN | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29884841 |
| Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. | Woods NT | NPJ genomic medicine | 2016 | PMID: 28781887 |
| A high frequency of BRCA mutations in young black women with breast cancer residing in Florida. | Pal T | Cancer | 2015 | PMID: 26287763 |
| Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations. | Martelotto LG | Genome biology | 2014 | PMID: 25348012 |
Text-mined citations for rs397507226 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.