This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.4649C>T (p.Thr1550Ile)
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.
(14)
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.
Uncertain significance
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.4649C>T (p.Thr1550Ile)
Variation ID: 55251 Accession: VCV000055251.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43074357 (GRCh38) [ NCBI UCSC ] 17: 41226374 (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 May 1, 2024 Jan 18, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.4649C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Thr1550Ile missense NM_001407571.1:c.4436C>T NP_001394500.1:p.Thr1479Ile missense NM_001407581.1:c.4715C>T NP_001394510.1:p.Thr1572Ile missense NM_001407582.1:c.4715C>T NP_001394511.1:p.Thr1572Ile missense NM_001407583.1:c.4712C>T NP_001394512.1:p.Thr1571Ile missense NM_001407585.1:c.4712C>T NP_001394514.1:p.Thr1571Ile missense NM_001407587.1:c.4712C>T NP_001394516.1:p.Thr1571Ile missense NM_001407590.1:c.4709C>T NP_001394519.1:p.Thr1570Ile missense NM_001407591.1:c.4709C>T NP_001394520.1:p.Thr1570Ile missense NM_001407593.1:c.4649C>T NP_001394522.1:p.Thr1550Ile missense NM_001407594.1:c.4649C>T NP_001394523.1:p.Thr1550Ile missense NM_001407596.1:c.4649C>T NP_001394525.1:p.Thr1550Ile missense NM_001407597.1:c.4649C>T NP_001394526.1:p.Thr1550Ile missense NM_001407598.1:c.4649C>T NP_001394527.1:p.Thr1550Ile missense NM_001407602.1:c.4649C>T NP_001394531.1:p.Thr1550Ile missense NM_001407603.1:c.4649C>T NP_001394532.1:p.Thr1550Ile missense NM_001407605.1:c.4649C>T NP_001394534.1:p.Thr1550Ile missense NM_001407610.1:c.4646C>T NP_001394539.1:p.Thr1549Ile missense NM_001407611.1:c.4646C>T NP_001394540.1:p.Thr1549Ile missense NM_001407612.1:c.4646C>T NP_001394541.1:p.Thr1549Ile missense NM_001407613.1:c.4646C>T NP_001394542.1:p.Thr1549Ile missense NM_001407614.1:c.4646C>T NP_001394543.1:p.Thr1549Ile missense NM_001407615.1:c.4646C>T NP_001394544.1:p.Thr1549Ile missense NM_001407616.1:c.4646C>T NP_001394545.1:p.Thr1549Ile missense NM_001407617.1:c.4646C>T NP_001394546.1:p.Thr1549Ile missense NM_001407618.1:c.4646C>T NP_001394547.1:p.Thr1549Ile missense NM_001407619.1:c.4646C>T NP_001394548.1:p.Thr1549Ile missense NM_001407620.1:c.4646C>T NP_001394549.1:p.Thr1549Ile missense NM_001407621.1:c.4646C>T NP_001394550.1:p.Thr1549Ile missense NM_001407622.1:c.4646C>T NP_001394551.1:p.Thr1549Ile missense NM_001407623.1:c.4646C>T NP_001394552.1:p.Thr1549Ile missense NM_001407624.1:c.4646C>T NP_001394553.1:p.Thr1549Ile missense NM_001407625.1:c.4646C>T NP_001394554.1:p.Thr1549Ile missense NM_001407626.1:c.4646C>T NP_001394555.1:p.Thr1549Ile missense NM_001407627.1:c.4643C>T NP_001394556.1:p.Thr1548Ile missense NM_001407628.1:c.4643C>T NP_001394557.1:p.Thr1548Ile missense NM_001407629.1:c.4643C>T NP_001394558.1:p.Thr1548Ile missense NM_001407630.1:c.4643C>T NP_001394559.1:p.Thr1548Ile missense NM_001407631.1:c.4643C>T NP_001394560.1:p.Thr1548Ile missense NM_001407632.1:c.4643C>T NP_001394561.1:p.Thr1548Ile missense NM_001407633.1:c.4643C>T NP_001394562.1:p.Thr1548Ile missense NM_001407634.1:c.4643C>T NP_001394563.1:p.Thr1548Ile missense NM_001407635.1:c.4643C>T NP_001394564.1:p.Thr1548Ile missense NM_001407636.1:c.4643C>T NP_001394565.1:p.Thr1548Ile missense NM_001407637.1:c.4643C>T NP_001394566.1:p.Thr1548Ile missense NM_001407638.1:c.4643C>T NP_001394567.1:p.Thr1548Ile missense NM_001407639.1:c.4643C>T NP_001394568.1:p.Thr1548Ile missense NM_001407640.1:c.4643C>T NP_001394569.1:p.Thr1548Ile missense NM_001407641.1:c.4643C>T NP_001394570.1:p.Thr1548Ile missense NM_001407642.1:c.4643C>T NP_001394571.1:p.Thr1548Ile missense NM_001407644.1:c.4640C>T NP_001394573.1:p.Thr1547Ile missense NM_001407645.1:c.4640C>T NP_001394574.1:p.Thr1547Ile missense NM_001407646.1:c.4637C>T NP_001394575.1:p.Thr1546Ile missense NM_001407647.1:c.4634C>T NP_001394576.1:p.Thr1545Ile missense NM_001407648.1:c.4592C>T NP_001394577.1:p.Thr1531Ile missense NM_001407649.1:c.4589C>T NP_001394578.1:p.Thr1530Ile missense NM_001407652.1:c.4649C>T NP_001394581.1:p.Thr1550Ile missense NM_001407653.1:c.4571C>T NP_001394582.1:p.Thr1524Ile missense NM_001407654.1:c.4571C>T NP_001394583.1:p.Thr1524Ile missense NM_001407655.1:c.4571C>T NP_001394584.1:p.Thr1524Ile missense NM_001407656.1:c.4568C>T NP_001394585.1:p.Thr1523Ile missense NM_001407657.1:c.4568C>T NP_001394586.1:p.Thr1523Ile missense NM_001407658.1:c.4568C>T NP_001394587.1:p.Thr1523Ile missense NM_001407659.1:c.4565C>T NP_001394588.1:p.Thr1522Ile missense NM_001407660.1:c.4565C>T NP_001394589.1:p.Thr1522Ile missense NM_001407661.1:c.4565C>T NP_001394590.1:p.Thr1522Ile missense NM_001407662.1:c.4565C>T NP_001394591.1:p.Thr1522Ile missense NM_001407663.1:c.4565C>T NP_001394592.1:p.Thr1522Ile missense NM_001407664.1:c.4526C>T NP_001394593.1:p.Thr1509Ile missense NM_001407665.1:c.4526C>T NP_001394594.1:p.Thr1509Ile missense NM_001407666.1:c.4526C>T NP_001394595.1:p.Thr1509Ile missense NM_001407667.1:c.4526C>T NP_001394596.1:p.Thr1509Ile missense NM_001407668.1:c.4526C>T NP_001394597.1:p.Thr1509Ile missense NM_001407669.1:c.4526C>T NP_001394598.1:p.Thr1509Ile missense NM_001407670.1:c.4523C>T NP_001394599.1:p.Thr1508Ile missense NM_001407671.1:c.4523C>T NP_001394600.1:p.Thr1508Ile missense NM_001407672.1:c.4523C>T NP_001394601.1:p.Thr1508Ile missense NM_001407673.1:c.4523C>T NP_001394602.1:p.Thr1508Ile missense NM_001407674.1:c.4523C>T NP_001394603.1:p.Thr1508Ile missense NM_001407675.1:c.4523C>T NP_001394604.1:p.Thr1508Ile missense NM_001407676.1:c.4523C>T NP_001394605.1:p.Thr1508Ile missense NM_001407677.1:c.4523C>T NP_001394606.1:p.Thr1508Ile missense NM_001407678.1:c.4523C>T NP_001394607.1:p.Thr1508Ile missense NM_001407679.1:c.4523C>T NP_001394608.1:p.Thr1508Ile missense NM_001407680.1:c.4523C>T NP_001394609.1:p.Thr1508Ile missense NM_001407681.1:c.4520C>T NP_001394610.1:p.Thr1507Ile missense NM_001407682.1:c.4520C>T NP_001394611.1:p.Thr1507Ile missense NM_001407683.1:c.4520C>T NP_001394612.1:p.Thr1507Ile missense NM_001407684.1:c.4649C>T NP_001394613.1:p.Thr1550Ile missense NM_001407685.1:c.4520C>T NP_001394614.1:p.Thr1507Ile missense NM_001407686.1:c.4520C>T NP_001394615.1:p.Thr1507Ile missense NM_001407687.1:c.4520C>T NP_001394616.1:p.Thr1507Ile missense NM_001407688.1:c.4520C>T NP_001394617.1:p.Thr1507Ile missense NM_001407689.1:c.4520C>T NP_001394618.1:p.Thr1507Ile missense NM_001407690.1:c.4517C>T NP_001394619.1:p.Thr1506Ile missense NM_001407691.1:c.4517C>T NP_001394620.1:p.Thr1506Ile missense NM_001407692.1:c.4508C>T NP_001394621.1:p.Thr1503Ile missense NM_001407694.1:c.4508C>T NP_001394623.1:p.Thr1503Ile missense NM_001407695.1:c.4508C>T NP_001394624.1:p.Thr1503Ile missense NM_001407696.1:c.4508C>T NP_001394625.1:p.Thr1503Ile missense NM_001407697.1:c.4508C>T NP_001394626.1:p.Thr1503Ile missense NM_001407698.1:c.4508C>T NP_001394627.1:p.Thr1503Ile missense NM_001407724.1:c.4508C>T NP_001394653.1:p.Thr1503Ile missense NM_001407725.1:c.4508C>T NP_001394654.1:p.Thr1503Ile missense NM_001407726.1:c.4508C>T NP_001394655.1:p.Thr1503Ile missense NM_001407727.1:c.4508C>T NP_001394656.1:p.Thr1503Ile missense NM_001407728.1:c.4508C>T NP_001394657.1:p.Thr1503Ile missense NM_001407729.1:c.4508C>T NP_001394658.1:p.Thr1503Ile missense NM_001407730.1:c.4508C>T NP_001394659.1:p.Thr1503Ile missense NM_001407731.1:c.4508C>T NP_001394660.1:p.Thr1503Ile missense NM_001407732.1:c.4505C>T NP_001394661.1:p.Thr1502Ile missense NM_001407733.1:c.4505C>T NP_001394662.1:p.Thr1502Ile missense NM_001407734.1:c.4505C>T NP_001394663.1:p.Thr1502Ile missense NM_001407735.1:c.4505C>T NP_001394664.1:p.Thr1502Ile missense NM_001407736.1:c.4505C>T NP_001394665.1:p.Thr1502Ile missense NM_001407737.1:c.4505C>T NP_001394666.1:p.Thr1502Ile missense NM_001407738.1:c.4505C>T NP_001394667.1:p.Thr1502Ile missense NM_001407739.1:c.4505C>T NP_001394668.1:p.Thr1502Ile missense NM_001407740.1:c.4505C>T NP_001394669.1:p.Thr1502Ile missense NM_001407741.1:c.4505C>T NP_001394670.1:p.Thr1502Ile missense NM_001407742.1:c.4505C>T NP_001394671.1:p.Thr1502Ile missense NM_001407743.1:c.4505C>T NP_001394672.1:p.Thr1502Ile missense NM_001407744.1:c.4505C>T NP_001394673.1:p.Thr1502Ile missense NM_001407745.1:c.4505C>T NP_001394674.1:p.Thr1502Ile missense NM_001407746.1:c.4505C>T NP_001394675.1:p.Thr1502Ile missense NM_001407747.1:c.4505C>T NP_001394676.1:p.Thr1502Ile missense NM_001407748.1:c.4505C>T NP_001394677.1:p.Thr1502Ile missense NM_001407749.1:c.4505C>T NP_001394678.1:p.Thr1502Ile missense NM_001407750.1:c.4505C>T NP_001394679.1:p.Thr1502Ile missense NM_001407751.1:c.4505C>T NP_001394680.1:p.Thr1502Ile missense NM_001407752.1:c.4505C>T NP_001394681.1:p.Thr1502Ile missense NM_001407838.1:c.4502C>T NP_001394767.1:p.Thr1501Ile missense NM_001407839.1:c.4502C>T NP_001394768.1:p.Thr1501Ile missense NM_001407841.1:c.4502C>T NP_001394770.1:p.Thr1501Ile missense NM_001407842.1:c.4502C>T NP_001394771.1:p.Thr1501Ile missense NM_001407843.1:c.4502C>T NP_001394772.1:p.Thr1501Ile missense NM_001407844.1:c.4502C>T NP_001394773.1:p.Thr1501Ile missense NM_001407845.1:c.4502C>T NP_001394774.1:p.Thr1501Ile missense NM_001407846.1:c.4502C>T NP_001394775.1:p.Thr1501Ile missense NM_001407847.1:c.4502C>T NP_001394776.1:p.Thr1501Ile missense NM_001407848.1:c.4502C>T NP_001394777.1:p.Thr1501Ile missense NM_001407849.1:c.4502C>T NP_001394778.1:p.Thr1501Ile missense NM_001407850.1:c.4502C>T NP_001394779.1:p.Thr1501Ile missense NM_001407851.1:c.4502C>T NP_001394780.1:p.Thr1501Ile missense NM_001407852.1:c.4502C>T NP_001394781.1:p.Thr1501Ile missense NM_001407853.1:c.4502C>T NP_001394782.1:p.Thr1501Ile missense NM_001407854.1:c.4649C>T NP_001394783.1:p.Thr1550Ile missense NM_001407858.1:c.4646C>T NP_001394787.1:p.Thr1549Ile missense NM_001407859.1:c.4646C>T NP_001394788.1:p.Thr1549Ile missense NM_001407860.1:c.4646C>T NP_001394789.1:p.Thr1549Ile missense NM_001407861.1:c.4643C>T NP_001394790.1:p.Thr1548Ile missense NM_001407862.1:c.4448C>T NP_001394791.1:p.Thr1483Ile missense NM_001407863.1:c.4523C>T NP_001394792.1:p.Thr1508Ile missense NM_001407874.1:c.4442C>T NP_001394803.1:p.Thr1481Ile missense NM_001407875.1:c.4442C>T NP_001394804.1:p.Thr1481Ile missense NM_001407879.1:c.4439C>T NP_001394808.1:p.Thr1480Ile missense NM_001407881.1:c.4439C>T NP_001394810.1:p.Thr1480Ile missense NM_001407882.1:c.4439C>T NP_001394811.1:p.Thr1480Ile missense NM_001407884.1:c.4439C>T NP_001394813.1:p.Thr1480Ile missense NM_001407885.1:c.4439C>T NP_001394814.1:p.Thr1480Ile missense NM_001407886.1:c.4439C>T NP_001394815.1:p.Thr1480Ile missense NM_001407887.1:c.4439C>T NP_001394816.1:p.Thr1480Ile missense NM_001407889.1:c.4439C>T NP_001394818.1:p.Thr1480Ile missense NM_001407894.1:c.4436C>T NP_001394823.1:p.Thr1479Ile missense NM_001407895.1:c.4436C>T NP_001394824.1:p.Thr1479Ile missense NM_001407896.1:c.4436C>T NP_001394825.1:p.Thr1479Ile missense NM_001407897.1:c.4436C>T NP_001394826.1:p.Thr1479Ile missense NM_001407898.1:c.4436C>T NP_001394827.1:p.Thr1479Ile missense NM_001407899.1:c.4436C>T NP_001394828.1:p.Thr1479Ile missense NM_001407900.1:c.4436C>T NP_001394829.1:p.Thr1479Ile missense NM_001407902.1:c.4436C>T NP_001394831.1:p.Thr1479Ile missense NM_001407904.1:c.4436C>T NP_001394833.1:p.Thr1479Ile missense NM_001407906.1:c.4436C>T NP_001394835.1:p.Thr1479Ile missense NM_001407907.1:c.4436C>T NP_001394836.1:p.Thr1479Ile missense NM_001407908.1:c.4436C>T NP_001394837.1:p.Thr1479Ile missense NM_001407909.1:c.4436C>T NP_001394838.1:p.Thr1479Ile missense NM_001407910.1:c.4436C>T NP_001394839.1:p.Thr1479Ile missense NM_001407915.1:c.4433C>T NP_001394844.1:p.Thr1478Ile missense NM_001407916.1:c.4433C>T NP_001394845.1:p.Thr1478Ile missense NM_001407917.1:c.4433C>T NP_001394846.1:p.Thr1478Ile missense NM_001407918.1:c.4433C>T NP_001394847.1:p.Thr1478Ile missense NM_001407919.1:c.4526C>T NP_001394848.1:p.Thr1509Ile missense NM_001407920.1:c.4385C>T NP_001394849.1:p.Thr1462Ile missense NM_001407921.1:c.4385C>T NP_001394850.1:p.Thr1462Ile missense NM_001407922.1:c.4385C>T NP_001394851.1:p.Thr1462Ile missense NM_001407923.1:c.4385C>T NP_001394852.1:p.Thr1462Ile missense NM_001407924.1:c.4385C>T NP_001394853.1:p.Thr1462Ile missense NM_001407925.1:c.4385C>T NP_001394854.1:p.Thr1462Ile missense NM_001407926.1:c.4385C>T NP_001394855.1:p.Thr1462Ile missense NM_001407927.1:c.4382C>T NP_001394856.1:p.Thr1461Ile missense NM_001407928.1:c.4382C>T NP_001394857.1:p.Thr1461Ile missense NM_001407929.1:c.4382C>T NP_001394858.1:p.Thr1461Ile missense NM_001407930.1:c.4382C>T NP_001394859.1:p.Thr1461Ile missense NM_001407931.1:c.4382C>T NP_001394860.1:p.Thr1461Ile missense NM_001407932.1:c.4382C>T NP_001394861.1:p.Thr1461Ile missense NM_001407933.1:c.4382C>T NP_001394862.1:p.Thr1461Ile missense NM_001407934.1:c.4379C>T NP_001394863.1:p.Thr1460Ile missense NM_001407935.1:c.4379C>T NP_001394864.1:p.Thr1460Ile missense NM_001407936.1:c.4379C>T NP_001394865.1:p.Thr1460Ile missense NM_001407937.1:c.4526C>T NP_001394866.1:p.Thr1509Ile missense NM_001407938.1:c.4526C>T NP_001394867.1:p.Thr1509Ile missense NM_001407939.1:c.4523C>T NP_001394868.1:p.Thr1508Ile missense NM_001407940.1:c.4523C>T NP_001394869.1:p.Thr1508Ile missense NM_001407941.1:c.4520C>T NP_001394870.1:p.Thr1507Ile missense NM_001407942.1:c.4508C>T NP_001394871.1:p.Thr1503Ile missense NM_001407943.1:c.4505C>T NP_001394872.1:p.Thr1502Ile missense NM_001407944.1:c.4505C>T NP_001394873.1:p.Thr1502Ile missense NM_001407945.1:c.4505C>T NP_001394874.1:p.Thr1502Ile missense NM_001407946.1:c.4316C>T NP_001394875.1:p.Thr1439Ile missense NM_001407947.1:c.4316C>T NP_001394876.1:p.Thr1439Ile missense NM_001407948.1:c.4316C>T NP_001394877.1:p.Thr1439Ile missense NM_001407949.1:c.4316C>T NP_001394878.1:p.Thr1439Ile missense NM_001407950.1:c.4313C>T NP_001394879.1:p.Thr1438Ile missense NM_001407951.1:c.4313C>T NP_001394880.1:p.Thr1438Ile missense NM_001407952.1:c.4313C>T NP_001394881.1:p.Thr1438Ile missense NM_001407953.1:c.4313C>T NP_001394882.1:p.Thr1438Ile missense NM_001407954.1:c.4313C>T NP_001394883.1:p.Thr1438Ile missense NM_001407955.1:c.4313C>T NP_001394884.1:p.Thr1438Ile missense NM_001407956.1:c.4310C>T NP_001394885.1:p.Thr1437Ile missense NM_001407957.1:c.4310C>T NP_001394886.1:p.Thr1437Ile missense NM_001407958.1:c.4310C>T NP_001394887.1:p.Thr1437Ile missense NM_001407959.1:c.4268C>T NP_001394888.1:p.Thr1423Ile missense NM_001407960.1:c.4265C>T NP_001394889.1:p.Thr1422Ile missense NM_001407962.1:c.4265C>T NP_001394891.1:p.Thr1422Ile missense NM_001407963.1:c.4262C>T NP_001394892.1:p.Thr1421Ile missense NM_001407965.1:c.4142C>T NP_001394894.1:p.Thr1381Ile missense NM_001407966.1:c.3761C>T NP_001394895.1:p.Thr1254Ile missense NM_001407967.1:c.3758C>T NP_001394896.1:p.Thr1253Ile missense NM_001407968.1:c.2045C>T NP_001394897.1:p.Thr682Ile missense NM_001407969.1:c.2042C>T NP_001394898.1:p.Thr681Ile missense NM_001407970.1:c.1406C>T NP_001394899.1:p.Thr469Ile missense NM_001407971.1:c.1406C>T NP_001394900.1:p.Thr469Ile missense NM_001407972.1:c.1403C>T NP_001394901.1:p.Thr468Ile missense NM_001407973.1:c.1340C>T NP_001394902.1:p.Thr447Ile missense NM_001407974.1:c.1340C>T NP_001394903.1:p.Thr447Ile missense NM_001407975.1:c.1340C>T NP_001394904.1:p.Thr447Ile missense NM_001407976.1:c.1340C>T NP_001394905.1:p.Thr447Ile missense NM_001407977.1:c.1340C>T NP_001394906.1:p.Thr447Ile missense NM_001407978.1:c.1340C>T NP_001394907.1:p.Thr447Ile missense NM_001407979.1:c.1337C>T NP_001394908.1:p.Thr446Ile missense NM_001407980.1:c.1337C>T NP_001394909.1:p.Thr446Ile missense NM_001407981.1:c.1337C>T NP_001394910.1:p.Thr446Ile missense NM_001407982.1:c.1337C>T NP_001394911.1:p.Thr446Ile missense NM_001407983.1:c.1337C>T NP_001394912.1:p.Thr446Ile missense NM_001407984.1:c.1337C>T NP_001394913.1:p.Thr446Ile missense NM_001407985.1:c.1337C>T NP_001394914.1:p.Thr446Ile missense NM_001407986.1:c.1337C>T NP_001394915.1:p.Thr446Ile missense NM_001407990.1:c.1337C>T NP_001394919.1:p.Thr446Ile missense NM_001407991.1:c.1337C>T NP_001394920.1:p.Thr446Ile missense NM_001407992.1:c.1337C>T NP_001394921.1:p.Thr446Ile missense NM_001407993.1:c.1337C>T NP_001394922.1:p.Thr446Ile missense NM_001408392.1:c.1334C>T NP_001395321.1:p.Thr445Ile missense NM_001408396.1:c.1334C>T NP_001395325.1:p.Thr445Ile missense NM_001408397.1:c.1334C>T NP_001395326.1:p.Thr445Ile missense NM_001408398.1:c.1334C>T NP_001395327.1:p.Thr445Ile missense NM_001408399.1:c.1334C>T NP_001395328.1:p.Thr445Ile missense NM_001408400.1:c.1334C>T NP_001395329.1:p.Thr445Ile missense NM_001408401.1:c.1334C>T NP_001395330.1:p.Thr445Ile missense NM_001408402.1:c.1334C>T NP_001395331.1:p.Thr445Ile missense NM_001408403.1:c.1334C>T NP_001395332.1:p.Thr445Ile missense NM_001408404.1:c.1334C>T NP_001395333.1:p.Thr445Ile missense NM_001408406.1:c.1331C>T NP_001395335.1:p.Thr444Ile missense NM_001408407.1:c.1331C>T NP_001395336.1:p.Thr444Ile missense NM_001408408.1:c.1331C>T NP_001395337.1:p.Thr444Ile missense NM_001408409.1:c.1328C>T NP_001395338.1:p.Thr443Ile missense NM_001408410.1:c.1265C>T NP_001395339.1:p.Thr422Ile missense NM_001408411.1:c.1262C>T NP_001395340.1:p.Thr421Ile missense NM_001408412.1:c.1259C>T NP_001395341.1:p.Thr420Ile missense NM_001408413.1:c.1259C>T NP_001395342.1:p.Thr420Ile missense NM_001408414.1:c.1259C>T NP_001395343.1:p.Thr420Ile missense NM_001408415.1:c.1259C>T NP_001395344.1:p.Thr420Ile missense NM_001408416.1:c.1259C>T NP_001395345.1:p.Thr420Ile missense NM_001408418.1:c.1223C>T NP_001395347.1:p.Thr408Ile missense NM_001408419.1:c.1223C>T NP_001395348.1:p.Thr408Ile missense NM_001408420.1:c.1223C>T NP_001395349.1:p.Thr408Ile missense NM_001408421.1:c.1220C>T NP_001395350.1:p.Thr407Ile missense NM_001408422.1:c.1220C>T NP_001395351.1:p.Thr407Ile missense NM_001408423.1:c.1220C>T NP_001395352.1:p.Thr407Ile missense NM_001408424.1:c.1220C>T NP_001395353.1:p.Thr407Ile missense NM_001408425.1:c.1217C>T NP_001395354.1:p.Thr406Ile missense NM_001408426.1:c.1217C>T NP_001395355.1:p.Thr406Ile missense NM_001408427.1:c.1217C>T NP_001395356.1:p.Thr406Ile missense NM_001408428.1:c.1217C>T NP_001395357.1:p.Thr406Ile missense NM_001408429.1:c.1217C>T NP_001395358.1:p.Thr406Ile missense NM_001408430.1:c.1217C>T NP_001395359.1:p.Thr406Ile missense NM_001408431.1:c.1217C>T NP_001395360.1:p.Thr406Ile missense NM_001408432.1:c.1214C>T NP_001395361.1:p.Thr405Ile missense NM_001408433.1:c.1214C>T NP_001395362.1:p.Thr405Ile missense NM_001408434.1:c.1214C>T NP_001395363.1:p.Thr405Ile missense NM_001408435.1:c.1214C>T NP_001395364.1:p.Thr405Ile missense NM_001408436.1:c.1214C>T NP_001395365.1:p.Thr405Ile missense NM_001408437.1:c.1214C>T NP_001395366.1:p.Thr405Ile missense NM_001408438.1:c.1214C>T NP_001395367.1:p.Thr405Ile missense NM_001408439.1:c.1214C>T NP_001395368.1:p.Thr405Ile missense NM_001408440.1:c.1214C>T NP_001395369.1:p.Thr405Ile missense NM_001408441.1:c.1214C>T NP_001395370.1:p.Thr405Ile missense NM_001408442.1:c.1214C>T NP_001395371.1:p.Thr405Ile missense NM_001408443.1:c.1214C>T NP_001395372.1:p.Thr405Ile missense NM_001408444.1:c.1214C>T NP_001395373.1:p.Thr405Ile missense NM_001408445.1:c.1211C>T NP_001395374.1:p.Thr404Ile missense NM_001408446.1:c.1211C>T NP_001395375.1:p.Thr404Ile missense NM_001408447.1:c.1211C>T NP_001395376.1:p.Thr404Ile missense NM_001408448.1:c.1211C>T NP_001395377.1:p.Thr404Ile missense NM_001408450.1:c.1211C>T NP_001395379.1:p.Thr404Ile missense NM_001408451.1:c.1205C>T NP_001395380.1:p.Thr402Ile missense NM_001408452.1:c.1199C>T NP_001395381.1:p.Thr400Ile missense NM_001408453.1:c.1199C>T NP_001395382.1:p.Thr400Ile missense NM_001408454.1:c.1199C>T NP_001395383.1:p.Thr400Ile missense NM_001408455.1:c.1199C>T NP_001395384.1:p.Thr400Ile missense NM_001408456.1:c.1199C>T NP_001395385.1:p.Thr400Ile missense NM_001408457.1:c.1199C>T NP_001395386.1:p.Thr400Ile missense NM_001408458.1:c.1196C>T NP_001395387.1:p.Thr399Ile missense NM_001408459.1:c.1196C>T NP_001395388.1:p.Thr399Ile missense NM_001408460.1:c.1196C>T NP_001395389.1:p.Thr399Ile missense NM_001408461.1:c.1196C>T NP_001395390.1:p.Thr399Ile missense NM_001408462.1:c.1196C>T NP_001395391.1:p.Thr399Ile missense NM_001408463.1:c.1196C>T NP_001395392.1:p.Thr399Ile missense NM_001408464.1:c.1196C>T NP_001395393.1:p.Thr399Ile missense NM_001408465.1:c.1196C>T NP_001395394.1:p.Thr399Ile missense NM_001408466.1:c.1196C>T NP_001395395.1:p.Thr399Ile missense NM_001408467.1:c.1196C>T NP_001395396.1:p.Thr399Ile missense NM_001408468.1:c.1193C>T NP_001395397.1:p.Thr398Ile missense NM_001408469.1:c.1193C>T NP_001395398.1:p.Thr398Ile missense NM_001408470.1:c.1193C>T NP_001395399.1:p.Thr398Ile missense NM_001408472.1:c.1337C>T NP_001395401.1:p.Thr446Ile missense NM_001408473.1:c.1334C>T NP_001395402.1:p.Thr445Ile missense NM_001408474.1:c.1139C>T NP_001395403.1:p.Thr380Ile missense NM_001408475.1:c.1136C>T NP_001395404.1:p.Thr379Ile missense NM_001408476.1:c.1136C>T NP_001395405.1:p.Thr379Ile missense NM_001408478.1:c.1130C>T NP_001395407.1:p.Thr377Ile missense NM_001408479.1:c.1130C>T NP_001395408.1:p.Thr377Ile missense NM_001408480.1:c.1130C>T NP_001395409.1:p.Thr377Ile missense NM_001408481.1:c.1127C>T NP_001395410.1:p.Thr376Ile missense NM_001408482.1:c.1127C>T NP_001395411.1:p.Thr376Ile missense NM_001408483.1:c.1127C>T NP_001395412.1:p.Thr376Ile missense NM_001408484.1:c.1127C>T NP_001395413.1:p.Thr376Ile missense NM_001408485.1:c.1127C>T NP_001395414.1:p.Thr376Ile missense NM_001408489.1:c.1127C>T NP_001395418.1:p.Thr376Ile missense NM_001408490.1:c.1127C>T NP_001395419.1:p.Thr376Ile missense NM_001408491.1:c.1127C>T NP_001395420.1:p.Thr376Ile missense NM_001408492.1:c.1124C>T NP_001395421.1:p.Thr375Ile missense NM_001408493.1:c.1124C>T NP_001395422.1:p.Thr375Ile missense NM_001408494.1:c.1100C>T NP_001395423.1:p.Thr367Ile missense NM_001408495.1:c.1094C>T NP_001395424.1:p.Thr365Ile missense NM_001408496.1:c.1076C>T NP_001395425.1:p.Thr359Ile missense NM_001408497.1:c.1076C>T NP_001395426.1:p.Thr359Ile missense NM_001408498.1:c.1076C>T NP_001395427.1:p.Thr359Ile missense NM_001408499.1:c.1076C>T NP_001395428.1:p.Thr359Ile missense NM_001408500.1:c.1076C>T NP_001395429.1:p.Thr359Ile missense NM_001408501.1:c.1076C>T NP_001395430.1:p.Thr359Ile missense NM_001408502.1:c.1073C>T NP_001395431.1:p.Thr358Ile missense NM_001408503.1:c.1073C>T NP_001395432.1:p.Thr358Ile missense NM_001408504.1:c.1073C>T NP_001395433.1:p.Thr358Ile missense NM_001408505.1:c.1070C>T NP_001395434.1:p.Thr357Ile missense NM_001408506.1:c.1013C>T NP_001395435.1:p.Thr338Ile missense NM_001408507.1:c.1010C>T NP_001395436.1:p.Thr337Ile missense NM_001408508.1:c.1001C>T NP_001395437.1:p.Thr334Ile missense NM_001408509.1:c.998C>T NP_001395438.1:p.Thr333Ile missense NM_001408510.1:c.959C>T NP_001395439.1:p.Thr320Ile missense NM_001408511.1:c.956C>T NP_001395440.1:p.Thr319Ile missense NM_001408512.1:c.836C>T NP_001395441.1:p.Thr279Ile missense NM_007294.3(BRCA1):c.4649C>T missense NM_007297.4:c.4508C>T NP_009228.2:p.Thr1503Ile missense NM_007298.4:c.1337C>T NP_009229.2:p.Thr446Ile missense NM_007299.4:c.1337C>T NP_009230.2:p.Thr446Ile missense NM_007300.4:c.4712C>T NP_009231.2:p.Thr1571Ile missense NM_007304.2:c.1337C>T NP_009235.2:p.Thr446Ile missense NR_027676.2:n.4826C>T non-coding transcript variant NC_000017.11:g.43074357G>A NC_000017.10:g.41226374G>A NG_005905.2:g.143627C>T LRG_292:g.143627C>T LRG_292t1:c.4649C>T LRG_292p1:p.Thr1550Ile U14680.1:n.4768C>T - Protein change
- T1550I, T1503I, T446I, T1571I, T1254I, T1439I, T1506I, T1522I, T1524I, T1549I, T358I, T359I, T379I, T400I, T404I, T445I, T447I, T1253I, T1421I, T1480I, T1502I, T1507I, T1508I, T1530I, T1381I, T1422I, T1438I, T1460I, T1462I, T1483I, T1523I, T1531I, T1546I, T1547I, T320I, T333I, T398I, T406I, T421I, T422I, T443I, T682I, T1423I, T1437I, T1461I, T1478I, T1479I, T1481I, T1501I, T1509I, T1548I, T1572I, T279I, T334I, T337I, T338I, T376I, T377I, T380I, T399I, T402I, T408I, T420I, T469I, T1545I, T1570I, T319I, T357I, T365I, T367I, T375I, T405I, T407I, T444I, T468I, T681I
- Other names
-
p.T1550I:ACA>ATA
- Canonical SPDI
- NC_000017.11:43074356: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
Trans-Omics for Precision Medicine (TOPMed) 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 |
13040 | 14846 | |
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, multiple submitters, no conflicts
|
May 3, 2023 | RCV000048618.12 | |
| Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 28, 2023 | RCV000112373.9 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 24, 2023 | RCV000129109.16 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 18, 2024 | RCV000195394.12 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 8, 2020 | RCV001248951.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 26, 2021 | RCV002477174.1 |
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
(Jul 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV000679698.1
First in ClinVar: Oct 21, 2017 Last updated: Oct 21, 2017 |
|
|
|
Uncertain significance
(Jul 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
paternal
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001482788.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Not Specified
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422731.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Thr1550Ile variant (sometimes called p.Thr1571Ile) in BRCA1 has been reported in 1 pediatric individual with hyperdiploid acute lymphoblastic leukemia (PMID: 26580448), and was absent … (more)
The p.Thr1550Ile variant (sometimes called p.Thr1571Ile) in BRCA1 has been reported in 1 pediatric individual with hyperdiploid acute lymphoblastic leukemia (PMID: 26580448), and was absent from large population studies. This variant has also been reported as a VUS in ClinVar (Variation ID: 55251). In vitro functional studies provide some evidence that the p.Thr1550Ile variant may not reduce gene expression (PMID: 28781887). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The Threonine (Thr) at position 1550 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that this variant will affect binding to another protein (PMID: 23704879). In summary, the clinical significance of the p.Thr1550Ile variant is uncertain. ACMG/AMP Criteria applied: PM2, BS3_Supporting (Richards 2015). (less)
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Uncertain significance
(Jan 18, 2024)
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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
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000076631.13
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1550 of the BRCA1 protein (p.Thr1550Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1550 of the BRCA1 protein (p.Thr1550Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 10923033, 26580448). This variant is also known as T1571I. ClinVar contains an entry for this variant (Variation ID: 55251). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 28781887). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Jun 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
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All of Us Research Program, National Institutes of Health
Accession: SCV004817646.1
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)
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Comment:
This missense variant replaces threonine with isoleucine at codon 1550 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 1550 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). A transcription activation assay using transiently transfected mammalian cell has reported this variant as functional (PMID: 28781887). This variant has been reported in one individual affected with leukemia (PMID: 26580448). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.256 and 1.0595, respectively (PMID: 31131967). 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: 4
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Uncertain significance
(Apr 08, 2019)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428451.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Number of individuals with the variant: 1
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Uncertain significance
(Oct 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001442613.1
First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020 |
Comment:
Variant summary: BRCA1 c.4649C>T (p.Thr1550Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: BRCA1 c.4649C>T (p.Thr1550Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251282 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4649C>T has been reported in the literature in an individual affected with hyperdiploid ALL (acute lymphoblastic leukemia) (Zhang_2015). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. In transcriptional activation luciferase reporter assays, the variant was found to have similar activity that of wild type (Woods_2016). Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jun 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488717.2
First in ClinVar: Apr 01, 2014 Last updated: Dec 24, 2022 |
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Uncertain significance
(Aug 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Breast-ovarian cancer, familial, susceptibility to, 1 Pancreatic cancer, susceptibility to, 4 Fanconi anemia, complementation group S
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002785343.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jan 19, 2023)
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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: SCV000210182.14
First in ClinVar: Feb 24, 2015 Last updated: Feb 07, 2023 |
Comment:
Observed in individuals with pediatric cancer (Zhang et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed … (more)
Observed in individuals with pediatric cancer (Zhang et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (gnomAD); Published functional studies suggest this variant has no damaging effect: transcriptional activiation activity comparable to wildtype (Woods et al., 2016; Fernandes et al., 2019, Iversen et al., 2022); Also known as 4768C>T; This variant is associated with the following publications: (PMID: 15385441, 23704879, 19276368, 28781887, 31131967, 29884841, 31911673, 32377563, 35665744, 11301010, 9774970, 10220405, 31853058, 30765603, 26580448) (less)
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Uncertain significance
(May 03, 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: SCV000296308.5
First in ClinVar: Apr 01, 2014 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000013 (2/152198 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000013 (2/152198 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with pediatric leukemia (PMID: 26580448 (2015)). It is predicted to abolish a BRCA1 phosphorylation site in silico, but the effect of the predicted change on BRCA1 function is unknown (PMID: 23704879 (2013)). Functional studies show that this variant has a higher activity than a wild type control in an in vitro transcription activation assay (PMIDs: 28781887 (2016) and 30765603 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Mar 21, 2023)
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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: SCV000688507.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with isoleucine at codon 1550 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 1550 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). A transcription activation assay using transiently transfected mammalian cell has reported this variant as functional (PMID: 28781887). This variant has been reported in one individual affected with leukemia (PMID: 26580448). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.256 and 1.0595, respectively (PMID: 31131967). 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
(Jul 24, 2023)
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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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Ambry Genetics
Accession: SCV000183820.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.T1550I variant (also known as c.4649C>T), located in coding exon 13 of the BRCA1 gene, results from a C to T substitution at nucleotide … (more)
The p.T1550I variant (also known as c.4649C>T), located in coding exon 13 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4649. The threonine at codon 1550 is replaced by isoleucine, an amino acid with similar properties. This alteration has been predicted to be 'likely not pathogenic' based on functional data from a transcriptional activation luciferase reporter assay (Woods NT et al. NPJ Genom Med. 2016;1. pii: 16001). However, in another study, this alteration was associated with altered phosphorylation of a putative kinase binding motif using the NetworKIN algorithm (Tram E et al. PLoS ONE 2013; 8(5):e62468). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(May 29, 2002)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145139.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Western European
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
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Comment:
Comment:
The p.Thr1550Ile variant (sometimes called p.Thr1571Ile) in BRCA1 has been reported in 1 pediatric individual with hyperdiploid acute lymphoblastic leukemia (PMID: 26580448), and was absent from large population studies. This variant has also been reported as a VUS in ClinVar (Variation ID: 55251). In vitro functional studies provide some evidence that the p.Thr1550Ile variant may not reduce gene expression (PMID: 28781887). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The Threonine (Thr) at position 1550 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that this variant will affect binding to another protein (PMID: 23704879). In summary, the clinical significance of the p.Thr1550Ile variant is uncertain. ACMG/AMP Criteria applied: PM2, BS3_Supporting (Richards 2015).
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1550 of the BRCA1 protein (p.Thr1550Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 10923033, 26580448). This variant is also known as T1571I. ClinVar contains an entry for this variant (Variation ID: 55251). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 28781887). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces threonine with isoleucine at codon 1550 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). A transcription activation assay using transiently transfected mammalian cell has reported this variant as functional (PMID: 28781887). This variant has been reported in one individual affected with leukemia (PMID: 26580448). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.256 and 1.0595, respectively (PMID: 31131967). 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:
Variant summary: BRCA1 c.4649C>T (p.Thr1550Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251282 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4649C>T has been reported in the literature in an individual affected with hyperdiploid ALL (acute lymphoblastic leukemia) (Zhang_2015). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. In transcriptional activation luciferase reporter assays, the variant was found to have similar activity that of wild type (Woods_2016). Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
Observed in individuals with pediatric cancer (Zhang et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (gnomAD); Published functional studies suggest this variant has no damaging effect: transcriptional activiation activity comparable to wildtype (Woods et al., 2016; Fernandes et al., 2019, Iversen et al., 2022); Also known as 4768C>T; This variant is associated with the following publications: (PMID: 15385441, 23704879, 19276368, 28781887, 31131967, 29884841, 31911673, 32377563, 35665744, 11301010, 9774970, 10220405, 31853058, 30765603, 26580448)
Comment:
The frequency of this variant in the general population, 0.000013 (2/152198 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with pediatric leukemia (PMID: 26580448 (2015)). It is predicted to abolish a BRCA1 phosphorylation site in silico, but the effect of the predicted change on BRCA1 function is unknown (PMID: 23704879 (2013)). Functional studies show that this variant has a higher activity than a wild type control in an in vitro transcription activation assay (PMIDs: 28781887 (2016) and 30765603 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces threonine with isoleucine at codon 1550 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). A transcription activation assay using transiently transfected mammalian cell has reported this variant as functional (PMID: 28781887). This variant has been reported in one individual affected with leukemia (PMID: 26580448). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.256 and 1.0595, respectively (PMID: 31131967). 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:
The p.T1550I variant (also known as c.4649C>T), located in coding exon 13 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4649. The threonine at codon 1550 is replaced by isoleucine, an amino acid with similar properties. This alteration has been predicted to be 'likely not pathogenic' based on functional data from a transcriptional activation luciferase reporter assay (Woods NT et al. NPJ Genom Med. 2016;1. pii: 16001). However, in another study, this alteration was associated with altered phosphorylation of a putative kinase binding motif using the NetworKIN algorithm (Tram E et al. PLoS ONE 2013; 8(5):e62468). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The p.Thr1550Ile variant (sometimes called p.Thr1571Ile) in BRCA1 has been reported in 1 pediatric individual with hyperdiploid acute lymphoblastic leukemia (PMID: 26580448), and was absent from large population studies. This variant has also been reported as a VUS in ClinVar (Variation ID: 55251). In vitro functional studies provide some evidence that the p.Thr1550Ile variant may not reduce gene expression (PMID: 28781887). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The Threonine (Thr) at position 1550 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that this variant will affect binding to another protein (PMID: 23704879). In summary, the clinical significance of the p.Thr1550Ile variant is uncertain. ACMG/AMP Criteria applied: PM2, BS3_Supporting (Richards 2015).
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1550 of the BRCA1 protein (p.Thr1550Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 10923033, 26580448). This variant is also known as T1571I. ClinVar contains an entry for this variant (Variation ID: 55251). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 28781887). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces threonine with isoleucine at codon 1550 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). A transcription activation assay using transiently transfected mammalian cell has reported this variant as functional (PMID: 28781887). This variant has been reported in one individual affected with leukemia (PMID: 26580448). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.256 and 1.0595, respectively (PMID: 31131967). 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:
Variant summary: BRCA1 c.4649C>T (p.Thr1550Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251282 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4649C>T has been reported in the literature in an individual affected with hyperdiploid ALL (acute lymphoblastic leukemia) (Zhang_2015). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. In transcriptional activation luciferase reporter assays, the variant was found to have similar activity that of wild type (Woods_2016). Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
Observed in individuals with pediatric cancer (Zhang et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (gnomAD); Published functional studies suggest this variant has no damaging effect: transcriptional activiation activity comparable to wildtype (Woods et al., 2016; Fernandes et al., 2019, Iversen et al., 2022); Also known as 4768C>T; This variant is associated with the following publications: (PMID: 15385441, 23704879, 19276368, 28781887, 31131967, 29884841, 31911673, 32377563, 35665744, 11301010, 9774970, 10220405, 31853058, 30765603, 26580448)
Comment:
The frequency of this variant in the general population, 0.000013 (2/152198 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with pediatric leukemia (PMID: 26580448 (2015)). It is predicted to abolish a BRCA1 phosphorylation site in silico, but the effect of the predicted change on BRCA1 function is unknown (PMID: 23704879 (2013)). Functional studies show that this variant has a higher activity than a wild type control in an in vitro transcription activation assay (PMIDs: 28781887 (2016) and 30765603 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces threonine with isoleucine at codon 1550 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). A transcription activation assay using transiently transfected mammalian cell has reported this variant as functional (PMID: 28781887). This variant has been reported in one individual affected with leukemia (PMID: 26580448). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.256 and 1.0595, respectively (PMID: 31131967). 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:
The p.T1550I variant (also known as c.4649C>T), located in coding exon 13 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4649. The threonine at codon 1550 is replaced by isoleucine, an amino acid with similar properties. This alteration has been predicted to be 'likely not pathogenic' based on functional data from a transcriptional activation luciferase reporter assay (Woods NT et al. NPJ Genom Med. 2016;1. pii: 16001). However, in another study, this alteration was associated with altered phosphorylation of a putative kinase binding motif using the NetworKIN algorithm (Tram E et al. PLoS ONE 2013; 8(5):e62468). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. | Parsons MT | Human mutation | 2019 | PMID: 31131967 |
| 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 |
| Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. | Woods NT | NPJ genomic medicine | 2016 | PMID: 28781887 |
| Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
| Missense variants of uncertain significance (VUS) altering the phosphorylation patterns of BRCA1 and BRCA2. | Tram E | PloS one | 2013 | PMID: 23704879 |
| CDC25B mediates rapamycin-induced oncogenic responses in cancer cells. | Chen RQ | Cancer research | 2009 | PMID: 19276368 |
| The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/3adb27cc-518e-4c2e-a58c-7e39081ea026 | - | - | - | - |
Text-mined citations for rs80357076 ...
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.