The p.T1691I pathogenic variant (also known as c.5072C>T), located in coding exon 15 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5072. The threonine at codon 1691 is replaced by isoleucine, an amino acid with similar properties. Multiple RNA studies show that this alteration results in out-of-frame skipping of coding exon 15 (also called Exon 17 in the literature), however this event may be incomplete (Ambry internal data; Ahlborn LB et al. Breast Cancer Res. Treat. 2015 Apr; 150(2):289-98). One downstream functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay and that this event may be, at least in part, due to an RNA defect (Findlay GM et al. Nature. 2018 10;562:217-222). In addition, multiple protein functional assays, including a cell-based transcription activation assay and a homology directed DNA repair assay found that this protein effect was non-functional leading to the possibility of a combined deleterious RNA and protein effect (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90; Petitalot A et al. Mol. Cancer Res. 2019 01;17:54-69). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5072C>T (p.Thr1691Ile)
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.
(13)
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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.
Pathogenic/Likely pathogenic
13
criteria provided, multiple submitters, no conflicts
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.5072C>T (p.Thr1691Ile)
Variation ID: 37628 Accession: VCV000037628.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43067610 (GRCh38) [ NCBI UCSC ] 17: 41219627 (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 Apr 1, 2014 Oct 8, 2024 Aug 6, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.5072C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Thr1691Ile missense NM_001407571.1:c.4859C>T NP_001394500.1:p.Thr1620Ile missense NM_001407581.1:c.5138C>T NP_001394510.1:p.Thr1713Ile missense NM_001407582.1:c.5138C>T NP_001394511.1:p.Thr1713Ile missense NM_001407583.1:c.5135C>T NP_001394512.1:p.Thr1712Ile missense NM_001407585.1:c.5135C>T NP_001394514.1:p.Thr1712Ile missense NM_001407587.1:c.5135C>T NP_001394516.1:p.Thr1712Ile missense NM_001407590.1:c.5132C>T NP_001394519.1:p.Thr1711Ile missense NM_001407591.1:c.5132C>T NP_001394520.1:p.Thr1711Ile missense NM_001407593.1:c.5072C>T NP_001394522.1:p.Thr1691Ile missense NM_001407594.1:c.5072C>T NP_001394523.1:p.Thr1691Ile missense NM_001407596.1:c.5072C>T NP_001394525.1:p.Thr1691Ile missense NM_001407597.1:c.5072C>T NP_001394526.1:p.Thr1691Ile missense NM_001407598.1:c.5072C>T NP_001394527.1:p.Thr1691Ile missense NM_001407602.1:c.5072C>T NP_001394531.1:p.Thr1691Ile missense NM_001407603.1:c.5072C>T NP_001394532.1:p.Thr1691Ile missense NM_001407605.1:c.5072C>T NP_001394534.1:p.Thr1691Ile missense NM_001407610.1:c.5069C>T NP_001394539.1:p.Thr1690Ile missense NM_001407611.1:c.5069C>T NP_001394540.1:p.Thr1690Ile missense NM_001407612.1:c.5069C>T NP_001394541.1:p.Thr1690Ile missense NM_001407613.1:c.5069C>T NP_001394542.1:p.Thr1690Ile missense NM_001407614.1:c.5069C>T NP_001394543.1:p.Thr1690Ile missense NM_001407615.1:c.5069C>T NP_001394544.1:p.Thr1690Ile missense NM_001407616.1:c.5069C>T NP_001394545.1:p.Thr1690Ile missense NM_001407617.1:c.5069C>T NP_001394546.1:p.Thr1690Ile missense NM_001407618.1:c.5069C>T NP_001394547.1:p.Thr1690Ile missense NM_001407619.1:c.5069C>T NP_001394548.1:p.Thr1690Ile missense NM_001407620.1:c.5069C>T NP_001394549.1:p.Thr1690Ile missense NM_001407621.1:c.5069C>T NP_001394550.1:p.Thr1690Ile missense NM_001407622.1:c.5069C>T NP_001394551.1:p.Thr1690Ile missense NM_001407623.1:c.5069C>T NP_001394552.1:p.Thr1690Ile missense NM_001407624.1:c.5069C>T NP_001394553.1:p.Thr1690Ile missense NM_001407625.1:c.5069C>T NP_001394554.1:p.Thr1690Ile missense NM_001407626.1:c.5069C>T NP_001394555.1:p.Thr1690Ile missense NM_001407627.1:c.5066C>T NP_001394556.1:p.Thr1689Ile missense NM_001407628.1:c.5066C>T NP_001394557.1:p.Thr1689Ile missense NM_001407629.1:c.5066C>T NP_001394558.1:p.Thr1689Ile missense NM_001407630.1:c.5066C>T NP_001394559.1:p.Thr1689Ile missense NM_001407631.1:c.5066C>T NP_001394560.1:p.Thr1689Ile missense NM_001407632.1:c.5066C>T NP_001394561.1:p.Thr1689Ile missense NM_001407633.1:c.5066C>T NP_001394562.1:p.Thr1689Ile missense NM_001407634.1:c.5066C>T NP_001394563.1:p.Thr1689Ile missense NM_001407635.1:c.5066C>T NP_001394564.1:p.Thr1689Ile missense NM_001407636.1:c.5066C>T NP_001394565.1:p.Thr1689Ile missense NM_001407637.1:c.5066C>T NP_001394566.1:p.Thr1689Ile missense NM_001407638.1:c.5066C>T NP_001394567.1:p.Thr1689Ile missense NM_001407639.1:c.5066C>T NP_001394568.1:p.Thr1689Ile missense NM_001407640.1:c.5066C>T NP_001394569.1:p.Thr1689Ile missense NM_001407641.1:c.5066C>T NP_001394570.1:p.Thr1689Ile missense NM_001407642.1:c.5066C>T NP_001394571.1:p.Thr1689Ile missense NM_001407644.1:c.5063C>T NP_001394573.1:p.Thr1688Ile missense NM_001407645.1:c.5063C>T NP_001394574.1:p.Thr1688Ile missense NM_001407646.1:c.5060C>T NP_001394575.1:p.Thr1687Ile missense NM_001407647.1:c.5057C>T NP_001394576.1:p.Thr1686Ile missense NM_001407648.1:c.5015C>T NP_001394577.1:p.Thr1672Ile missense NM_001407649.1:c.5012C>T NP_001394578.1:p.Thr1671Ile missense NM_001407652.1:c.5072C>T NP_001394581.1:p.Thr1691Ile missense NM_001407653.1:c.4994C>T NP_001394582.1:p.Thr1665Ile missense NM_001407654.1:c.4994C>T NP_001394583.1:p.Thr1665Ile missense NM_001407655.1:c.4994C>T NP_001394584.1:p.Thr1665Ile missense NM_001407656.1:c.4991C>T NP_001394585.1:p.Thr1664Ile missense NM_001407657.1:c.4991C>T NP_001394586.1:p.Thr1664Ile missense NM_001407658.1:c.4991C>T NP_001394587.1:p.Thr1664Ile missense NM_001407659.1:c.4988C>T NP_001394588.1:p.Thr1663Ile missense NM_001407660.1:c.4988C>T NP_001394589.1:p.Thr1663Ile missense NM_001407661.1:c.4988C>T NP_001394590.1:p.Thr1663Ile missense NM_001407662.1:c.4988C>T NP_001394591.1:p.Thr1663Ile missense NM_001407663.1:c.4988C>T NP_001394592.1:p.Thr1663Ile missense NM_001407664.1:c.4949C>T NP_001394593.1:p.Thr1650Ile missense NM_001407665.1:c.4949C>T NP_001394594.1:p.Thr1650Ile missense NM_001407666.1:c.4949C>T NP_001394595.1:p.Thr1650Ile missense NM_001407667.1:c.4949C>T NP_001394596.1:p.Thr1650Ile missense NM_001407668.1:c.4949C>T NP_001394597.1:p.Thr1650Ile missense NM_001407669.1:c.4949C>T NP_001394598.1:p.Thr1650Ile missense NM_001407670.1:c.4946C>T NP_001394599.1:p.Thr1649Ile missense NM_001407671.1:c.4946C>T NP_001394600.1:p.Thr1649Ile missense NM_001407672.1:c.4946C>T NP_001394601.1:p.Thr1649Ile missense NM_001407673.1:c.4946C>T NP_001394602.1:p.Thr1649Ile missense NM_001407674.1:c.4946C>T NP_001394603.1:p.Thr1649Ile missense NM_001407675.1:c.4946C>T NP_001394604.1:p.Thr1649Ile missense NM_001407676.1:c.4946C>T NP_001394605.1:p.Thr1649Ile missense NM_001407677.1:c.4946C>T NP_001394606.1:p.Thr1649Ile missense NM_001407678.1:c.4946C>T NP_001394607.1:p.Thr1649Ile missense NM_001407679.1:c.4946C>T NP_001394608.1:p.Thr1649Ile missense NM_001407680.1:c.4946C>T NP_001394609.1:p.Thr1649Ile missense NM_001407681.1:c.4943C>T NP_001394610.1:p.Thr1648Ile missense NM_001407682.1:c.4943C>T NP_001394611.1:p.Thr1648Ile missense NM_001407683.1:c.4943C>T NP_001394612.1:p.Thr1648Ile missense NM_001407684.1:c.5072C>T NP_001394613.1:p.Thr1691Ile missense NM_001407685.1:c.4943C>T NP_001394614.1:p.Thr1648Ile missense NM_001407686.1:c.4943C>T NP_001394615.1:p.Thr1648Ile missense NM_001407687.1:c.4943C>T NP_001394616.1:p.Thr1648Ile missense NM_001407688.1:c.4943C>T NP_001394617.1:p.Thr1648Ile missense NM_001407689.1:c.4943C>T NP_001394618.1:p.Thr1648Ile missense NM_001407690.1:c.4940C>T NP_001394619.1:p.Thr1647Ile missense NM_001407691.1:c.4940C>T NP_001394620.1:p.Thr1647Ile missense NM_001407692.1:c.4931C>T NP_001394621.1:p.Thr1644Ile missense NM_001407694.1:c.4931C>T NP_001394623.1:p.Thr1644Ile missense NM_001407695.1:c.4931C>T NP_001394624.1:p.Thr1644Ile missense NM_001407696.1:c.4931C>T NP_001394625.1:p.Thr1644Ile missense NM_001407697.1:c.4931C>T NP_001394626.1:p.Thr1644Ile missense NM_001407698.1:c.4931C>T NP_001394627.1:p.Thr1644Ile missense NM_001407724.1:c.4931C>T NP_001394653.1:p.Thr1644Ile missense NM_001407725.1:c.4931C>T NP_001394654.1:p.Thr1644Ile missense NM_001407726.1:c.4931C>T NP_001394655.1:p.Thr1644Ile missense NM_001407727.1:c.4931C>T NP_001394656.1:p.Thr1644Ile missense NM_001407728.1:c.4931C>T NP_001394657.1:p.Thr1644Ile missense NM_001407729.1:c.4931C>T NP_001394658.1:p.Thr1644Ile missense NM_001407730.1:c.4931C>T NP_001394659.1:p.Thr1644Ile missense NM_001407731.1:c.4931C>T NP_001394660.1:p.Thr1644Ile missense NM_001407732.1:c.4928C>T NP_001394661.1:p.Thr1643Ile missense NM_001407733.1:c.4928C>T NP_001394662.1:p.Thr1643Ile missense NM_001407734.1:c.4928C>T NP_001394663.1:p.Thr1643Ile missense NM_001407735.1:c.4928C>T NP_001394664.1:p.Thr1643Ile missense NM_001407736.1:c.4928C>T NP_001394665.1:p.Thr1643Ile missense NM_001407737.1:c.4928C>T NP_001394666.1:p.Thr1643Ile missense NM_001407738.1:c.4928C>T NP_001394667.1:p.Thr1643Ile missense NM_001407739.1:c.4928C>T NP_001394668.1:p.Thr1643Ile missense NM_001407740.1:c.4928C>T NP_001394669.1:p.Thr1643Ile missense NM_001407741.1:c.4928C>T NP_001394670.1:p.Thr1643Ile missense NM_001407742.1:c.4928C>T NP_001394671.1:p.Thr1643Ile missense NM_001407743.1:c.4928C>T NP_001394672.1:p.Thr1643Ile missense NM_001407744.1:c.4928C>T NP_001394673.1:p.Thr1643Ile missense NM_001407745.1:c.4928C>T NP_001394674.1:p.Thr1643Ile missense NM_001407746.1:c.4928C>T NP_001394675.1:p.Thr1643Ile missense NM_001407747.1:c.4928C>T NP_001394676.1:p.Thr1643Ile missense NM_001407748.1:c.4928C>T NP_001394677.1:p.Thr1643Ile missense NM_001407749.1:c.4928C>T NP_001394678.1:p.Thr1643Ile missense NM_001407750.1:c.4928C>T NP_001394679.1:p.Thr1643Ile missense NM_001407751.1:c.4928C>T NP_001394680.1:p.Thr1643Ile missense NM_001407752.1:c.4928C>T NP_001394681.1:p.Thr1643Ile missense NM_001407838.1:c.4925C>T NP_001394767.1:p.Thr1642Ile missense NM_001407839.1:c.4925C>T NP_001394768.1:p.Thr1642Ile missense NM_001407841.1:c.4925C>T NP_001394770.1:p.Thr1642Ile missense NM_001407842.1:c.4925C>T NP_001394771.1:p.Thr1642Ile missense NM_001407843.1:c.4925C>T NP_001394772.1:p.Thr1642Ile missense NM_001407844.1:c.4925C>T NP_001394773.1:p.Thr1642Ile missense NM_001407845.1:c.4925C>T NP_001394774.1:p.Thr1642Ile missense NM_001407846.1:c.4925C>T NP_001394775.1:p.Thr1642Ile missense NM_001407847.1:c.4925C>T NP_001394776.1:p.Thr1642Ile missense NM_001407848.1:c.4925C>T NP_001394777.1:p.Thr1642Ile missense NM_001407849.1:c.4925C>T NP_001394778.1:p.Thr1642Ile missense NM_001407850.1:c.4925C>T NP_001394779.1:p.Thr1642Ile missense NM_001407851.1:c.4925C>T NP_001394780.1:p.Thr1642Ile missense NM_001407852.1:c.4925C>T NP_001394781.1:p.Thr1642Ile missense NM_001407853.1:c.4925C>T NP_001394782.1:p.Thr1642Ile missense NM_001407854.1:c.5072C>T NP_001394783.1:p.Thr1691Ile missense NM_001407858.1:c.5069C>T NP_001394787.1:p.Thr1690Ile missense NM_001407859.1:c.5069C>T NP_001394788.1:p.Thr1690Ile missense NM_001407860.1:c.5069C>T NP_001394789.1:p.Thr1690Ile missense NM_001407861.1:c.5066C>T NP_001394790.1:p.Thr1689Ile missense NM_001407862.1:c.4871C>T NP_001394791.1:p.Thr1624Ile missense NM_001407863.1:c.4946C>T NP_001394792.1:p.Thr1649Ile missense NM_001407874.1:c.4865C>T NP_001394803.1:p.Thr1622Ile missense NM_001407875.1:c.4865C>T NP_001394804.1:p.Thr1622Ile missense NM_001407879.1:c.4862C>T NP_001394808.1:p.Thr1621Ile missense NM_001407881.1:c.4862C>T NP_001394810.1:p.Thr1621Ile missense NM_001407882.1:c.4862C>T NP_001394811.1:p.Thr1621Ile missense NM_001407884.1:c.4862C>T NP_001394813.1:p.Thr1621Ile missense NM_001407885.1:c.4862C>T NP_001394814.1:p.Thr1621Ile missense NM_001407886.1:c.4862C>T NP_001394815.1:p.Thr1621Ile missense NM_001407887.1:c.4862C>T NP_001394816.1:p.Thr1621Ile missense NM_001407889.1:c.4862C>T NP_001394818.1:p.Thr1621Ile missense NM_001407894.1:c.4859C>T NP_001394823.1:p.Thr1620Ile missense NM_001407895.1:c.4859C>T NP_001394824.1:p.Thr1620Ile missense NM_001407896.1:c.4859C>T NP_001394825.1:p.Thr1620Ile missense NM_001407897.1:c.4859C>T NP_001394826.1:p.Thr1620Ile missense NM_001407898.1:c.4859C>T NP_001394827.1:p.Thr1620Ile missense NM_001407899.1:c.4859C>T NP_001394828.1:p.Thr1620Ile missense NM_001407900.1:c.4859C>T NP_001394829.1:p.Thr1620Ile missense NM_001407902.1:c.4859C>T NP_001394831.1:p.Thr1620Ile missense NM_001407904.1:c.4859C>T NP_001394833.1:p.Thr1620Ile missense NM_001407906.1:c.4859C>T NP_001394835.1:p.Thr1620Ile missense NM_001407907.1:c.4859C>T NP_001394836.1:p.Thr1620Ile missense NM_001407908.1:c.4859C>T NP_001394837.1:p.Thr1620Ile missense NM_001407909.1:c.4859C>T NP_001394838.1:p.Thr1620Ile missense NM_001407910.1:c.4859C>T NP_001394839.1:p.Thr1620Ile missense NM_001407915.1:c.4856C>T NP_001394844.1:p.Thr1619Ile missense NM_001407916.1:c.4856C>T NP_001394845.1:p.Thr1619Ile missense NM_001407917.1:c.4856C>T NP_001394846.1:p.Thr1619Ile missense NM_001407918.1:c.4856C>T NP_001394847.1:p.Thr1619Ile missense NM_001407919.1:c.4949C>T NP_001394848.1:p.Thr1650Ile missense NM_001407920.1:c.4808C>T NP_001394849.1:p.Thr1603Ile missense NM_001407921.1:c.4808C>T NP_001394850.1:p.Thr1603Ile missense NM_001407922.1:c.4808C>T NP_001394851.1:p.Thr1603Ile missense NM_001407923.1:c.4808C>T NP_001394852.1:p.Thr1603Ile missense NM_001407924.1:c.4808C>T NP_001394853.1:p.Thr1603Ile missense NM_001407925.1:c.4808C>T NP_001394854.1:p.Thr1603Ile missense NM_001407926.1:c.4808C>T NP_001394855.1:p.Thr1603Ile missense NM_001407927.1:c.4805C>T NP_001394856.1:p.Thr1602Ile missense NM_001407928.1:c.4805C>T NP_001394857.1:p.Thr1602Ile missense NM_001407929.1:c.4805C>T NP_001394858.1:p.Thr1602Ile missense NM_001407930.1:c.4805C>T NP_001394859.1:p.Thr1602Ile missense NM_001407931.1:c.4805C>T NP_001394860.1:p.Thr1602Ile missense NM_001407932.1:c.4805C>T NP_001394861.1:p.Thr1602Ile missense NM_001407933.1:c.4805C>T NP_001394862.1:p.Thr1602Ile missense NM_001407934.1:c.4802C>T NP_001394863.1:p.Thr1601Ile missense NM_001407935.1:c.4802C>T NP_001394864.1:p.Thr1601Ile missense NM_001407936.1:c.4802C>T NP_001394865.1:p.Thr1601Ile missense NM_001407937.1:c.4949C>T NP_001394866.1:p.Thr1650Ile missense NM_001407938.1:c.4949C>T NP_001394867.1:p.Thr1650Ile missense NM_001407939.1:c.4946C>T NP_001394868.1:p.Thr1649Ile missense NM_001407940.1:c.4946C>T NP_001394869.1:p.Thr1649Ile missense NM_001407941.1:c.4943C>T NP_001394870.1:p.Thr1648Ile missense NM_001407942.1:c.4931C>T NP_001394871.1:p.Thr1644Ile missense NM_001407943.1:c.4928C>T NP_001394872.1:p.Thr1643Ile missense NM_001407944.1:c.4928C>T NP_001394873.1:p.Thr1643Ile missense NM_001407945.1:c.4928C>T NP_001394874.1:p.Thr1643Ile missense NM_001407946.1:c.4739C>T NP_001394875.1:p.Thr1580Ile missense NM_001407947.1:c.4739C>T NP_001394876.1:p.Thr1580Ile missense NM_001407948.1:c.4739C>T NP_001394877.1:p.Thr1580Ile missense NM_001407949.1:c.4739C>T NP_001394878.1:p.Thr1580Ile missense NM_001407950.1:c.4736C>T NP_001394879.1:p.Thr1579Ile missense NM_001407951.1:c.4736C>T NP_001394880.1:p.Thr1579Ile missense NM_001407952.1:c.4736C>T NP_001394881.1:p.Thr1579Ile missense NM_001407953.1:c.4736C>T NP_001394882.1:p.Thr1579Ile missense NM_001407954.1:c.4736C>T NP_001394883.1:p.Thr1579Ile missense NM_001407955.1:c.4736C>T NP_001394884.1:p.Thr1579Ile missense NM_001407956.1:c.4733C>T NP_001394885.1:p.Thr1578Ile missense NM_001407957.1:c.4733C>T NP_001394886.1:p.Thr1578Ile missense NM_001407958.1:c.4733C>T NP_001394887.1:p.Thr1578Ile missense NM_001407959.1:c.4691C>T NP_001394888.1:p.Thr1564Ile missense NM_001407960.1:c.4688C>T NP_001394889.1:p.Thr1563Ile missense NM_001407962.1:c.4688C>T NP_001394891.1:p.Thr1563Ile missense NM_001407963.1:c.4685C>T NP_001394892.1:p.Thr1562Ile missense NM_001407964.1:c.4610C>T NP_001394893.1:p.Thr1537Ile missense NM_001407965.1:c.4565C>T NP_001394894.1:p.Thr1522Ile missense NM_001407966.1:c.4184C>T NP_001394895.1:p.Thr1395Ile missense NM_001407967.1:c.4181C>T NP_001394896.1:p.Thr1394Ile missense NM_001407968.1:c.2468C>T NP_001394897.1:p.Thr823Ile missense NM_001407969.1:c.2465C>T NP_001394898.1:p.Thr822Ile missense NM_001407970.1:c.1829C>T NP_001394899.1:p.Thr610Ile missense NM_001407971.1:c.1829C>T NP_001394900.1:p.Thr610Ile missense NM_001407972.1:c.1826C>T NP_001394901.1:p.Thr609Ile missense NM_001407973.1:c.1763C>T NP_001394902.1:p.Thr588Ile missense NM_001407974.1:c.1763C>T NP_001394903.1:p.Thr588Ile missense NM_001407975.1:c.1763C>T NP_001394904.1:p.Thr588Ile missense NM_001407976.1:c.1763C>T NP_001394905.1:p.Thr588Ile missense NM_001407977.1:c.1763C>T NP_001394906.1:p.Thr588Ile missense NM_001407978.1:c.1763C>T NP_001394907.1:p.Thr588Ile missense NM_001407979.1:c.1760C>T NP_001394908.1:p.Thr587Ile missense NM_001407980.1:c.1760C>T NP_001394909.1:p.Thr587Ile missense NM_001407981.1:c.1760C>T NP_001394910.1:p.Thr587Ile missense NM_001407982.1:c.1760C>T NP_001394911.1:p.Thr587Ile missense NM_001407983.1:c.1760C>T NP_001394912.1:p.Thr587Ile missense NM_001407984.1:c.1760C>T NP_001394913.1:p.Thr587Ile missense NM_001407985.1:c.1760C>T NP_001394914.1:p.Thr587Ile missense NM_001407986.1:c.1760C>T NP_001394915.1:p.Thr587Ile missense NM_001407990.1:c.1760C>T NP_001394919.1:p.Thr587Ile missense NM_001407991.1:c.1760C>T NP_001394920.1:p.Thr587Ile missense NM_001407992.1:c.1760C>T NP_001394921.1:p.Thr587Ile missense NM_001407993.1:c.1760C>T NP_001394922.1:p.Thr587Ile missense NM_001408392.1:c.1757C>T NP_001395321.1:p.Thr586Ile missense NM_001408396.1:c.1757C>T NP_001395325.1:p.Thr586Ile missense NM_001408397.1:c.1757C>T NP_001395326.1:p.Thr586Ile missense NM_001408398.1:c.1757C>T NP_001395327.1:p.Thr586Ile missense NM_001408399.1:c.1757C>T NP_001395328.1:p.Thr586Ile missense NM_001408400.1:c.1757C>T NP_001395329.1:p.Thr586Ile missense NM_001408401.1:c.1757C>T NP_001395330.1:p.Thr586Ile missense NM_001408402.1:c.1757C>T NP_001395331.1:p.Thr586Ile missense NM_001408403.1:c.1757C>T NP_001395332.1:p.Thr586Ile missense NM_001408404.1:c.1757C>T NP_001395333.1:p.Thr586Ile missense NM_001408406.1:c.1754C>T NP_001395335.1:p.Thr585Ile missense NM_001408407.1:c.1754C>T NP_001395336.1:p.Thr585Ile missense NM_001408408.1:c.1754C>T NP_001395337.1:p.Thr585Ile missense NM_001408409.1:c.1751C>T NP_001395338.1:p.Thr584Ile missense NM_001408410.1:c.1688C>T NP_001395339.1:p.Thr563Ile missense NM_001408411.1:c.1685C>T NP_001395340.1:p.Thr562Ile missense NM_001408412.1:c.1682C>T NP_001395341.1:p.Thr561Ile missense NM_001408413.1:c.1682C>T NP_001395342.1:p.Thr561Ile missense NM_001408414.1:c.1682C>T NP_001395343.1:p.Thr561Ile missense NM_001408415.1:c.1682C>T NP_001395344.1:p.Thr561Ile missense NM_001408416.1:c.1682C>T NP_001395345.1:p.Thr561Ile missense NM_001408418.1:c.1646C>T NP_001395347.1:p.Thr549Ile missense NM_001408419.1:c.1646C>T NP_001395348.1:p.Thr549Ile missense NM_001408420.1:c.1646C>T NP_001395349.1:p.Thr549Ile missense NM_001408421.1:c.1643C>T NP_001395350.1:p.Thr548Ile missense NM_001408422.1:c.1643C>T NP_001395351.1:p.Thr548Ile missense NM_001408423.1:c.1643C>T NP_001395352.1:p.Thr548Ile missense NM_001408424.1:c.1643C>T NP_001395353.1:p.Thr548Ile missense NM_001408425.1:c.1640C>T NP_001395354.1:p.Thr547Ile missense NM_001408426.1:c.1640C>T NP_001395355.1:p.Thr547Ile missense NM_001408427.1:c.1640C>T NP_001395356.1:p.Thr547Ile missense NM_001408428.1:c.1640C>T NP_001395357.1:p.Thr547Ile missense NM_001408429.1:c.1640C>T NP_001395358.1:p.Thr547Ile missense NM_001408430.1:c.1640C>T NP_001395359.1:p.Thr547Ile missense NM_001408431.1:c.1640C>T NP_001395360.1:p.Thr547Ile missense NM_001408432.1:c.1637C>T NP_001395361.1:p.Thr546Ile missense NM_001408433.1:c.1637C>T NP_001395362.1:p.Thr546Ile missense NM_001408434.1:c.1637C>T NP_001395363.1:p.Thr546Ile missense NM_001408435.1:c.1637C>T NP_001395364.1:p.Thr546Ile missense NM_001408436.1:c.1637C>T NP_001395365.1:p.Thr546Ile missense NM_001408437.1:c.1637C>T NP_001395366.1:p.Thr546Ile missense NM_001408438.1:c.1637C>T NP_001395367.1:p.Thr546Ile missense NM_001408439.1:c.1637C>T NP_001395368.1:p.Thr546Ile missense NM_001408440.1:c.1637C>T NP_001395369.1:p.Thr546Ile missense NM_001408441.1:c.1637C>T NP_001395370.1:p.Thr546Ile missense NM_001408442.1:c.1637C>T NP_001395371.1:p.Thr546Ile missense NM_001408443.1:c.1637C>T NP_001395372.1:p.Thr546Ile missense NM_001408444.1:c.1637C>T NP_001395373.1:p.Thr546Ile missense NM_001408445.1:c.1634C>T NP_001395374.1:p.Thr545Ile missense NM_001408446.1:c.1634C>T NP_001395375.1:p.Thr545Ile missense NM_001408447.1:c.1634C>T NP_001395376.1:p.Thr545Ile missense NM_001408448.1:c.1634C>T NP_001395377.1:p.Thr545Ile missense NM_001408450.1:c.1634C>T NP_001395379.1:p.Thr545Ile missense NM_001408451.1:c.1628C>T NP_001395380.1:p.Thr543Ile missense NM_001408452.1:c.1622C>T NP_001395381.1:p.Thr541Ile missense NM_001408453.1:c.1622C>T NP_001395382.1:p.Thr541Ile missense NM_001408454.1:c.1622C>T NP_001395383.1:p.Thr541Ile missense NM_001408455.1:c.1622C>T NP_001395384.1:p.Thr541Ile missense NM_001408456.1:c.1622C>T NP_001395385.1:p.Thr541Ile missense NM_001408457.1:c.1622C>T NP_001395386.1:p.Thr541Ile missense NM_001408458.1:c.1619C>T NP_001395387.1:p.Thr540Ile missense NM_001408459.1:c.1619C>T NP_001395388.1:p.Thr540Ile missense NM_001408460.1:c.1619C>T NP_001395389.1:p.Thr540Ile missense NM_001408461.1:c.1619C>T NP_001395390.1:p.Thr540Ile missense NM_001408462.1:c.1619C>T NP_001395391.1:p.Thr540Ile missense NM_001408463.1:c.1619C>T NP_001395392.1:p.Thr540Ile missense NM_001408464.1:c.1619C>T NP_001395393.1:p.Thr540Ile missense NM_001408465.1:c.1619C>T NP_001395394.1:p.Thr540Ile missense NM_001408466.1:c.1619C>T NP_001395395.1:p.Thr540Ile missense NM_001408467.1:c.1619C>T NP_001395396.1:p.Thr540Ile missense NM_001408468.1:c.1616C>T NP_001395397.1:p.Thr539Ile missense NM_001408469.1:c.1616C>T NP_001395398.1:p.Thr539Ile missense NM_001408470.1:c.1616C>T NP_001395399.1:p.Thr539Ile missense NM_001408472.1:c.1760C>T NP_001395401.1:p.Thr587Ile missense NM_001408473.1:c.1757C>T NP_001395402.1:p.Thr586Ile missense NM_001408474.1:c.1562C>T NP_001395403.1:p.Thr521Ile missense NM_001408475.1:c.1559C>T NP_001395404.1:p.Thr520Ile missense NM_001408476.1:c.1559C>T NP_001395405.1:p.Thr520Ile missense NM_001408478.1:c.1553C>T NP_001395407.1:p.Thr518Ile missense NM_001408479.1:c.1553C>T NP_001395408.1:p.Thr518Ile missense NM_001408480.1:c.1553C>T NP_001395409.1:p.Thr518Ile missense NM_001408481.1:c.1550C>T NP_001395410.1:p.Thr517Ile missense NM_001408482.1:c.1550C>T NP_001395411.1:p.Thr517Ile missense NM_001408483.1:c.1550C>T NP_001395412.1:p.Thr517Ile missense NM_001408484.1:c.1550C>T NP_001395413.1:p.Thr517Ile missense NM_001408485.1:c.1550C>T NP_001395414.1:p.Thr517Ile missense NM_001408489.1:c.1550C>T NP_001395418.1:p.Thr517Ile missense NM_001408490.1:c.1550C>T NP_001395419.1:p.Thr517Ile missense NM_001408491.1:c.1550C>T NP_001395420.1:p.Thr517Ile missense NM_001408492.1:c.1547C>T NP_001395421.1:p.Thr516Ile missense NM_001408493.1:c.1547C>T NP_001395422.1:p.Thr516Ile missense NM_001408494.1:c.1523C>T NP_001395423.1:p.Thr508Ile missense NM_001408495.1:c.1517C>T NP_001395424.1:p.Thr506Ile missense NM_001408496.1:c.1499C>T NP_001395425.1:p.Thr500Ile missense NM_001408497.1:c.1499C>T NP_001395426.1:p.Thr500Ile missense NM_001408498.1:c.1499C>T NP_001395427.1:p.Thr500Ile missense NM_001408499.1:c.1499C>T NP_001395428.1:p.Thr500Ile missense NM_001408500.1:c.1499C>T NP_001395429.1:p.Thr500Ile missense NM_001408501.1:c.1499C>T NP_001395430.1:p.Thr500Ile missense NM_001408502.1:c.1496C>T NP_001395431.1:p.Thr499Ile missense NM_001408503.1:c.1496C>T NP_001395432.1:p.Thr499Ile missense NM_001408504.1:c.1496C>T NP_001395433.1:p.Thr499Ile missense NM_001408505.1:c.1493C>T NP_001395434.1:p.Thr498Ile missense NM_001408506.1:c.1436C>T NP_001395435.1:p.Thr479Ile missense NM_001408507.1:c.1433C>T NP_001395436.1:p.Thr478Ile missense NM_001408508.1:c.1424C>T NP_001395437.1:p.Thr475Ile missense NM_001408509.1:c.1421C>T NP_001395438.1:p.Thr474Ile missense NM_001408510.1:c.1382C>T NP_001395439.1:p.Thr461Ile missense NM_001408511.1:c.1379C>T NP_001395440.1:p.Thr460Ile missense NM_001408512.1:c.1259C>T NP_001395441.1:p.Thr420Ile missense NM_001408513.1:c.1232C>T NP_001395442.1:p.Thr411Ile missense NM_007297.4:c.4931C>T NP_009228.2:p.Thr1644Ile missense NM_007298.4:c.1760C>T NP_009229.2:p.Thr587Ile missense NM_007299.4:c.1760C>T NP_009230.2:p.Thr587Ile missense NM_007300.4:c.5135C>T NP_009231.2:p.Thr1712Ile missense NM_007304.2:c.1760C>T NP_009235.2:p.Thr587Ile missense NR_027676.2:n.5249C>T non-coding transcript variant NC_000017.11:g.43067610G>A NC_000017.10:g.41219627G>A NG_005905.2:g.150374C>T LRG_292:g.150374C>T LRG_292t1:c.5072C>T LRG_292p1:p.Thr1691Ile P38398:p.Thr1691Ile U14680.1:n.5191C>T - Protein change
- T1691I, T1712I, T1644I, T587I, T1395I, T1619I, T1620I, T1649I, T1650I, T1664I, T1672I, T1686I, T1688I, T1689I, T1711I, T1713I, T420I, T506I, T508I, T541I, T545I, T547I, T585I, T588I, T1522I, T1563I, T1602I, T1624I, T411I, T500I, T540I, T609I, T610I, T1394I, T1579I, T1601I, T1603I, T1621I, T1643I, T1647I, T1648I, T1663I, T1665I, T1690I, T460I, T474I, T475I, T478I, T499I, T517I, T518I, T521I, T543I, T548I, T586I, T823I, T1537I, T1562I, T1564I, T1578I, T1580I, T1622I, T1642I, T1671I, T1687I, T461I, T479I, T498I, T516I, T520I, T539I, T546I, T549I, T561I, T562I, T563I, T584I, T822I
- Other names
- -
- Canonical SPDI
- NC_000017.11:43067609:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
functionally_abnormal; Sequence Ontology [ SO:0002218]The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5072C>T, a MISSENSE variant, produced a function score of -1.4, corresponding to a functional classification of LOSS_OF_FUNCTION. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. [submitted by Brotman Baty Institute, University of Washington]
-
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.
- -
- 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 |
13050 | 14856 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (5) |
criteria provided, single submitter
|
- | RCV000031209.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 4, 2023 | RCV000048762.10 | |
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 6, 2024 | RCV000508659.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 22, 2021 | RCV000509720.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 4, 2022 | RCV002247402.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 1, 2019 | RCV001171419.4 | |
|
BRCA1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 31, 2024 | RCV004554633.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000608092.5
First in ClinVar: Oct 23, 2017 Last updated: May 01, 2024 |
Comment:
The p.T1691I pathogenic variant (also known as c.5072C>T), located in coding exon 15 of the BRCA1 gene, results from a C to T substitution at … (more)
The p.T1691I pathogenic variant (also known as c.5072C>T), located in coding exon 15 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5072. The threonine at codon 1691 is replaced by isoleucine, an amino acid with similar properties. Multiple RNA studies show that this alteration results in out-of-frame skipping of coding exon 15 (also called Exon 17 in the literature), however this event may be incomplete (Ambry internal data; Ahlborn LB et al. Breast Cancer Res. Treat. 2015 Apr; 150(2):289-98). One downstream functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay and that this event may be, at least in part, due to an RNA defect (Findlay GM et al. Nature. 2018 10;562:217-222). In addition, multiple protein functional assays, including a cell-based transcription activation assay and a homology directed DNA repair assay found that this protein effect was non-functional leading to the possibility of a combined deleterious RNA and protein effect (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90; Petitalot A et al. Mol. Cancer Res. 2019 01;17:54-69). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Likely pathogenic
(Aug 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568401.7
First in ClinVar: Apr 29, 2017 Last updated: Sep 16, 2024 |
Comment:
Exonic splice variant demonstrated to disrupt a natural splice donor site, leading to out-of-frame skipping of exon 16 (also known as exon 17 using alternate … (more)
Exonic splice variant demonstrated to disrupt a natural splice donor site, leading to out-of-frame skipping of exon 16 (also known as exon 17 using alternate numbering), as well as a minor amount of normal transcript, as shown via mini-gene assay (PMID: 25724305); Variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival, that accounts for splice impact (PMID: 30209399); Published functional studies measuring protein impact demonstrate a damaging effect: severe folding defect, compromised phosphopeptide selectivity and transcriptional activation, and non-functional homology directed DNA repair (PMID: 20516115, 35665744, 32546644); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with a personal history consistent with pathogenic variants in this gene (PMID: 29470806); Not observed in large population cohorts (gnomAD); Also known as 5191C>T; This variant is associated with the following publications: (PMID: 20516115, 17305420, 23867111, 25782689, 26913838, 28781887, 30209399, 30787465, 35665744, 31447099, 34597585, 30765603, 29470806, 31843900, 25348405, 32546644, 25724305) (less)
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Molecular Endocrinology Laboratory, Christian Medical College
Accession: SCV002003991.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
|
|
|
Likely pathogenic
(Jan 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000605900.3
First in ClinVar: Sep 30, 2017 Last updated: Jan 03, 2022 |
Comment:
In the published literature, this variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 29470806 (2018)). In addition, this variant … (more)
In the published literature, this variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 29470806 (2018)). In addition, this variant is reported to perturb normal mRNA splicing and affect BRCA1 transcriptional activity, growth complementation, peptide binding specificity, protein folding, and homologous repair activity based on experimental evidence (PMIDs: 20516115 (2010), 23867111 (2013), 25724305 (2015), 30257991 (2018), 30765603 (2019), and 31843900 (2019)). Furthermore, one study showed this variant apparently lost functional activity in a large-scale study using a haploid cell line (PMID: 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations. Variant is predicted to have a damaging effect on the protein and located in potentially critical domain of the protein.Therefore, we predict that the variant is likely pathogenic. (less)
|
|
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Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518587.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
|
Likely pathogenic
(Jan 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022073.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Oct 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000076775.8
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1691 of the BRCA1 protein (p.Thr1691Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1691 of the BRCA1 protein (p.Thr1691Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, pancreatic cancer, and/or prostate cancer (PMID: 29202330, 29470806, 31843900; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.5135C>T (p.Thr1712Ile). ClinVar contains an entry for this variant (Variation ID: 37628). An algorithm developed specifically for the BRCA1 gene suggests that this missense change is likely to be deleterious (PMID: 17305420). Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 28781887, 30209399, 30257991, 30765603). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25724305, 31843900). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(May 31, 2024)
|
no assertion criteria provided
Method: clinical testing
|
BRCA1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004742153.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The BRCA1 c.5072C>T variant is predicted to result in the amino acid substitution p.Thr1691Ile. This variant has been reported in individuals with breast and/or ovarian … (more)
The BRCA1 c.5072C>T variant is predicted to result in the amino acid substitution p.Thr1691Ile. This variant has been reported in individuals with breast and/or ovarian cancer and in a cohort of individuals with breast, ovarian, endometrial, or colon cancer (Table S2, Singh et al. 2018. PubMed ID: 29470806; Tables S6 and S8, Casadei et al. 2019. PubMed ID: 31843900; Caputo et al. 2021. PubMed ID: 34597585). Real time-PCR and in vitro experimental studies suggest this variant impacts mRNA splicing and protein function (see, for example, Ahlborn et al. 2015. PubMed ID: 25724305; Casadei et al. 2019. PubMed ID: 31843900; Supplementary Figure 1a, Lee et al. 2010. PubMed ID: 20516115; Tables 1 and S2, Bouwman et al. 2020. PubMed ID: 32546644). Alternative nucleotide changes affecting the same amino acid (p.Thr1691Lys, p.Thr1691Arg) have been reported in ClinVar as likely pathogenic/pathogenic (see ClinVar IDs:37627, 55373). This variant has not been reported in a large population database, indicating it is rare. In Clinvar, this variant is reported as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37628/). This variant is interpreted as pathogenic. (less)
|
|
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Pathogenic
(May 14, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Department of Medical Genetics, National Institute of Health
Accession: SCV000787744.1
First in ClinVar: Sep 27, 2014 Last updated: Sep 27, 2014 |
Comment:
We identified the heterozygous variant NM_007294.3:c.5072C>T (p.Thr1691Ile) in BRCA1 gene in a Congolese family with four female cases of breast/ovarian cancer over two generations. This … (more)
We identified the heterozygous variant NM_007294.3:c.5072C>T (p.Thr1691Ile) in BRCA1 gene in a Congolese family with four female cases of breast/ovarian cancer over two generations. This variant has previously been reported six times in families with hereditary breast and ovarian cancer syndrome. To date, there was a conflicting clinical significance of this variant in all databases from "Uncertain significance" in two reports to "likely pathogenic" in four others. This new report should contribute to improving the current pathogenicity ranking of this variant, c.5072C>T. (less)
Indication for testing: Hereditary breast and ovarian cancer syndrome
Age: 40-49 years
Sex: female
Ethnicity/Population group: African
Geographic origin: Congo
|
|
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Pathogenic
(Sep 01, 2019)
|
no assertion criteria provided
Method: research
|
Hereditary breast and ovarian cancer syndrome
Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
|
King Laboratory, University of Washington
Accession: SCV001251324.1
First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020
Comment:
Transcript analysis by cBROCA
|
|
|
|
not provided
(-)
|
no classification provided
Method: in vitro
|
Breast-ovarian cancer, familial 1
Affected status: not applicable
Allele origin:
not applicable
|
Brotman Baty Institute, University of Washington
Accession: SCV001244016.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
LOSS_OF_FUNCTION:-1.39646248988762
|
|
|
Uncertain significance
(Mar 06, 2007)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Older and outlier claim with insufficient supporting evidence
Source: ClinGen
|
Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000053809.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
|
|
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Uncertain significance
(Feb 20, 2004)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Older and outlier claim with insufficient supporting evidence
Source: ClinGen
|
Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145286.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 3
Ethnicity/Population group: African
|
|
| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
Exonic splice variant demonstrated to disrupt a natural splice donor site, leading to out-of-frame skipping of exon 16 (also known as exon 17 using alternate numbering), as well as a minor amount of normal transcript, as shown via mini-gene assay (PMID: 25724305); Variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival, that accounts for splice impact (PMID: 30209399); Published functional studies measuring protein impact demonstrate a damaging effect: severe folding defect, compromised phosphopeptide selectivity and transcriptional activation, and non-functional homology directed DNA repair (PMID: 20516115, 35665744, 32546644); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with a personal history consistent with pathogenic variants in this gene (PMID: 29470806); Not observed in large population cohorts (gnomAD); Also known as 5191C>T; This variant is associated with the following publications: (PMID: 20516115, 17305420, 23867111, 25782689, 26913838, 28781887, 30209399, 30787465, 35665744, 31447099, 34597585, 30765603, 29470806, 31843900, 25348405, 32546644, 25724305)
Comment:
In the published literature, this variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 29470806 (2018)). In addition, this variant is reported to perturb normal mRNA splicing and affect BRCA1 transcriptional activity, growth complementation, peptide binding specificity, protein folding, and homologous repair activity based on experimental evidence (PMIDs: 20516115 (2010), 23867111 (2013), 25724305 (2015), 30257991 (2018), 30765603 (2019), and 31843900 (2019)). Furthermore, one study showed this variant apparently lost functional activity in a large-scale study using a haploid cell line (PMID: 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations. Variant is predicted to have a damaging effect on the protein and located in potentially critical domain of the protein.Therefore, we predict that the variant is likely pathogenic.
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1691 of the BRCA1 protein (p.Thr1691Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, pancreatic cancer, and/or prostate cancer (PMID: 29202330, 29470806, 31843900; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.5135C>T (p.Thr1712Ile). ClinVar contains an entry for this variant (Variation ID: 37628). An algorithm developed specifically for the BRCA1 gene suggests that this missense change is likely to be deleterious (PMID: 17305420). Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 28781887, 30209399, 30257991, 30765603). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25724305, 31843900). For these reasons, this variant has been classified as Pathogenic.
Comment:
The BRCA1 c.5072C>T variant is predicted to result in the amino acid substitution p.Thr1691Ile. This variant has been reported in individuals with breast and/or ovarian cancer and in a cohort of individuals with breast, ovarian, endometrial, or colon cancer (Table S2, Singh et al. 2018. PubMed ID: 29470806; Tables S6 and S8, Casadei et al. 2019. PubMed ID: 31843900; Caputo et al. 2021. PubMed ID: 34597585). Real time-PCR and in vitro experimental studies suggest this variant impacts mRNA splicing and protein function (see, for example, Ahlborn et al. 2015. PubMed ID: 25724305; Casadei et al. 2019. PubMed ID: 31843900; Supplementary Figure 1a, Lee et al. 2010. PubMed ID: 20516115; Tables 1 and S2, Bouwman et al. 2020. PubMed ID: 32546644). Alternative nucleotide changes affecting the same amino acid (p.Thr1691Lys, p.Thr1691Arg) have been reported in ClinVar as likely pathogenic/pathogenic (see ClinVar IDs:37627, 55373). This variant has not been reported in a large population database, indicating it is rare. In Clinvar, this variant is reported as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37628/). This variant is interpreted as pathogenic.
Comment:
We identified the heterozygous variant NM_007294.3:c.5072C>T (p.Thr1691Ile) in BRCA1 gene in a Congolese family with four female cases of breast/ovarian cancer over two generations. This variant has previously been reported six times in families with hereditary breast and ovarian cancer syndrome. To date, there was a conflicting clinical significance of this variant in all databases from "Uncertain significance" in two reports to "likely pathogenic" in four others. This new report should contribute to improving the current pathogenicity ranking of this variant, c.5072C>T.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
functionally_abnormal
|
Method citation(s):
|
|
Brotman Baty Institute, University of Washington
Accession: SCV001244016.1
|
Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5072C>T, a MISSENSE variant, produced a function score of -1.4, corresponding to a functional classification of LOSS_OF_FUNCTION. … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5072C>T, a MISSENSE variant, produced a function score of -1.4, corresponding to a functional classification of LOSS_OF_FUNCTION. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. (less)
|
Comment:
The p.T1691I pathogenic variant (also known as c.5072C>T), located in coding exon 15 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5072. The threonine at codon 1691 is replaced by isoleucine, an amino acid with similar properties. Multiple RNA studies show that this alteration results in out-of-frame skipping of coding exon 15 (also called Exon 17 in the literature), however this event may be incomplete (Ambry internal data; Ahlborn LB et al. Breast Cancer Res. Treat. 2015 Apr; 150(2):289-98). One downstream functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay and that this event may be, at least in part, due to an RNA defect (Findlay GM et al. Nature. 2018 10;562:217-222). In addition, multiple protein functional assays, including a cell-based transcription activation assay and a homology directed DNA repair assay found that this protein effect was non-functional leading to the possibility of a combined deleterious RNA and protein effect (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90; Petitalot A et al. Mol. Cancer Res. 2019 01;17:54-69). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Exonic splice variant demonstrated to disrupt a natural splice donor site, leading to out-of-frame skipping of exon 16 (also known as exon 17 using alternate numbering), as well as a minor amount of normal transcript, as shown via mini-gene assay (PMID: 25724305); Variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival, that accounts for splice impact (PMID: 30209399); Published functional studies measuring protein impact demonstrate a damaging effect: severe folding defect, compromised phosphopeptide selectivity and transcriptional activation, and non-functional homology directed DNA repair (PMID: 20516115, 35665744, 32546644); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with a personal history consistent with pathogenic variants in this gene (PMID: 29470806); Not observed in large population cohorts (gnomAD); Also known as 5191C>T; This variant is associated with the following publications: (PMID: 20516115, 17305420, 23867111, 25782689, 26913838, 28781887, 30209399, 30787465, 35665744, 31447099, 34597585, 30765603, 29470806, 31843900, 25348405, 32546644, 25724305)
Comment:
In the published literature, this variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 29470806 (2018)). In addition, this variant is reported to perturb normal mRNA splicing and affect BRCA1 transcriptional activity, growth complementation, peptide binding specificity, protein folding, and homologous repair activity based on experimental evidence (PMIDs: 20516115 (2010), 23867111 (2013), 25724305 (2015), 30257991 (2018), 30765603 (2019), and 31843900 (2019)). Furthermore, one study showed this variant apparently lost functional activity in a large-scale study using a haploid cell line (PMID: 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations. Variant is predicted to have a damaging effect on the protein and located in potentially critical domain of the protein.Therefore, we predict that the variant is likely pathogenic.
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1691 of the BRCA1 protein (p.Thr1691Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, pancreatic cancer, and/or prostate cancer (PMID: 29202330, 29470806, 31843900; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.5135C>T (p.Thr1712Ile). ClinVar contains an entry for this variant (Variation ID: 37628). An algorithm developed specifically for the BRCA1 gene suggests that this missense change is likely to be deleterious (PMID: 17305420). Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 28781887, 30209399, 30257991, 30765603). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25724305, 31843900). For these reasons, this variant has been classified as Pathogenic.
Comment:
The BRCA1 c.5072C>T variant is predicted to result in the amino acid substitution p.Thr1691Ile. This variant has been reported in individuals with breast and/or ovarian cancer and in a cohort of individuals with breast, ovarian, endometrial, or colon cancer (Table S2, Singh et al. 2018. PubMed ID: 29470806; Tables S6 and S8, Casadei et al. 2019. PubMed ID: 31843900; Caputo et al. 2021. PubMed ID: 34597585). Real time-PCR and in vitro experimental studies suggest this variant impacts mRNA splicing and protein function (see, for example, Ahlborn et al. 2015. PubMed ID: 25724305; Casadei et al. 2019. PubMed ID: 31843900; Supplementary Figure 1a, Lee et al. 2010. PubMed ID: 20516115; Tables 1 and S2, Bouwman et al. 2020. PubMed ID: 32546644). Alternative nucleotide changes affecting the same amino acid (p.Thr1691Lys, p.Thr1691Arg) have been reported in ClinVar as likely pathogenic/pathogenic (see ClinVar IDs:37627, 55373). This variant has not been reported in a large population database, indicating it is rare. In Clinvar, this variant is reported as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37628/). This variant is interpreted as pathogenic.
Comment:
We identified the heterozygous variant NM_007294.3:c.5072C>T (p.Thr1691Ile) in BRCA1 gene in a Congolese family with four female cases of breast/ovarian cancer over two generations. This variant has previously been reported six times in families with hereditary breast and ovarian cancer syndrome. To date, there was a conflicting clinical significance of this variant in all databases from "Uncertain significance" in two reports to "likely pathogenic" in four others. This new report should contribute to improving the current pathogenicity ranking of this variant, c.5072C>T.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Characterization of splice-altering mutations in inherited predisposition to cancer. | Casadei S | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 31843900 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: [email protected] | American journal of human genetics | 2019 | PMID: 31447099 |
| Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation. | Fernandes VC | The Journal of biological chemistry | 2019 | PMID: 30765603 |
| Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk. | Petitalot A | Molecular cancer research : MCR | 2019 | PMID: 30257991 |
| Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
| Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. | Singh J | Breast cancer research and treatment | 2018 | PMID: 29470806 |
| Genetic alterations in sporadic triple negative breast cancer. | Pop LA | Breast (Edinburgh, Scotland) | 2018 | PMID: 29202330 |
| Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. | Woods NT | NPJ genomic medicine | 2016 | PMID: 28781887 |
| Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases. | Vail PJ | Journal of community genetics | 2015 | PMID: 25782689 |
| Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic. | Ahlborn LB | Breast cancer research and treatment | 2015 | PMID: 25724305 |
| A high-throughput functional complementation assay for classification of BRCA1 missense variants. | Bouwman P | Cancer discovery | 2013 | PMID: 23867111 |
| Structure-Function Of The Tumor Suppressor BRCA1. | Clark SL | Computational and structural biotechnology journal | 2012 | PMID: 22737296 |
| Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. | Lee MS | Cancer research | 2010 | PMID: 20516115 |
| Functional impact of missense variants in BRCA1 predicted by supervised learning. | Karchin R | PLoS computational biology | 2007 | PMID: 17305420 |
| https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
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Text-mined citations for rs80357034 ...
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 Nov 25, 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.