This missense variant replaces threonine with proline at codon 1349 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer case-control meta-analysis in 1/60465 cases and 1/53460 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000286). This variant has been identified in 5/282502 chromosomes 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.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.4045A>C (p.Thr1349Pro)
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.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)
Uncertain significance(4); Likely benign(1)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.4045A>C (p.Thr1349Pro)
Variation ID: 55084 Accession: VCV000055084.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43091486 (GRCh38) [ NCBI UCSC ] 17: 41243503 (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 Aug 28, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.4045A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Thr1349Pro missense NM_001407571.1:c.3832A>C NP_001394500.1:p.Thr1278Pro missense NM_001407581.1:c.4045A>C NP_001394510.1:p.Thr1349Pro missense NM_001407582.1:c.4045A>C NP_001394511.1:p.Thr1349Pro missense NM_001407583.1:c.4045A>C NP_001394512.1:p.Thr1349Pro missense NM_001407585.1:c.4045A>C NP_001394514.1:p.Thr1349Pro missense NM_001407587.1:c.4042A>C NP_001394516.1:p.Thr1348Pro missense NM_001407590.1:c.4042A>C NP_001394519.1:p.Thr1348Pro missense NM_001407591.1:c.4042A>C NP_001394520.1:p.Thr1348Pro missense NM_001407593.1:c.4045A>C NP_001394522.1:p.Thr1349Pro missense NM_001407594.1:c.4045A>C NP_001394523.1:p.Thr1349Pro missense NM_001407596.1:c.4045A>C NP_001394525.1:p.Thr1349Pro missense NM_001407597.1:c.4045A>C NP_001394526.1:p.Thr1349Pro missense NM_001407598.1:c.4045A>C NP_001394527.1:p.Thr1349Pro missense NM_001407602.1:c.4045A>C NP_001394531.1:p.Thr1349Pro missense NM_001407603.1:c.4045A>C NP_001394532.1:p.Thr1349Pro missense NM_001407605.1:c.4045A>C NP_001394534.1:p.Thr1349Pro missense NM_001407610.1:c.4042A>C NP_001394539.1:p.Thr1348Pro missense NM_001407611.1:c.4042A>C NP_001394540.1:p.Thr1348Pro missense NM_001407612.1:c.4042A>C NP_001394541.1:p.Thr1348Pro missense NM_001407613.1:c.4042A>C NP_001394542.1:p.Thr1348Pro missense NM_001407614.1:c.4042A>C NP_001394543.1:p.Thr1348Pro missense NM_001407615.1:c.4042A>C NP_001394544.1:p.Thr1348Pro missense NM_001407616.1:c.4045A>C NP_001394545.1:p.Thr1349Pro missense NM_001407617.1:c.4045A>C NP_001394546.1:p.Thr1349Pro missense NM_001407618.1:c.4045A>C NP_001394547.1:p.Thr1349Pro missense NM_001407619.1:c.4045A>C NP_001394548.1:p.Thr1349Pro missense NM_001407620.1:c.4045A>C NP_001394549.1:p.Thr1349Pro missense NM_001407621.1:c.4045A>C NP_001394550.1:p.Thr1349Pro missense NM_001407622.1:c.4045A>C NP_001394551.1:p.Thr1349Pro missense NM_001407623.1:c.4045A>C NP_001394552.1:p.Thr1349Pro missense NM_001407624.1:c.4045A>C NP_001394553.1:p.Thr1349Pro missense NM_001407625.1:c.4045A>C NP_001394554.1:p.Thr1349Pro missense NM_001407626.1:c.4045A>C NP_001394555.1:p.Thr1349Pro missense NM_001407627.1:c.4042A>C NP_001394556.1:p.Thr1348Pro missense NM_001407628.1:c.4042A>C NP_001394557.1:p.Thr1348Pro missense NM_001407629.1:c.4042A>C NP_001394558.1:p.Thr1348Pro missense NM_001407630.1:c.4042A>C NP_001394559.1:p.Thr1348Pro missense NM_001407631.1:c.4042A>C NP_001394560.1:p.Thr1348Pro missense NM_001407632.1:c.4042A>C NP_001394561.1:p.Thr1348Pro missense NM_001407633.1:c.4042A>C NP_001394562.1:p.Thr1348Pro missense NM_001407634.1:c.4042A>C NP_001394563.1:p.Thr1348Pro missense NM_001407635.1:c.4042A>C NP_001394564.1:p.Thr1348Pro missense NM_001407636.1:c.4042A>C NP_001394565.1:p.Thr1348Pro missense NM_001407637.1:c.4042A>C NP_001394566.1:p.Thr1348Pro missense NM_001407638.1:c.4042A>C NP_001394567.1:p.Thr1348Pro missense NM_001407639.1:c.4045A>C NP_001394568.1:p.Thr1349Pro missense NM_001407640.1:c.4045A>C NP_001394569.1:p.Thr1349Pro missense NM_001407641.1:c.4045A>C NP_001394570.1:p.Thr1349Pro missense NM_001407642.1:c.4045A>C NP_001394571.1:p.Thr1349Pro missense NM_001407644.1:c.4042A>C NP_001394573.1:p.Thr1348Pro missense NM_001407645.1:c.4042A>C NP_001394574.1:p.Thr1348Pro missense NM_001407646.1:c.4036A>C NP_001394575.1:p.Thr1346Pro missense NM_001407647.1:c.4036A>C NP_001394576.1:p.Thr1346Pro missense NM_001407648.1:c.3922A>C NP_001394577.1:p.Thr1308Pro missense NM_001407649.1:c.3919A>C NP_001394578.1:p.Thr1307Pro missense NM_001407652.1:c.4045A>C NP_001394581.1:p.Thr1349Pro missense NM_001407653.1:c.3967A>C NP_001394582.1:p.Thr1323Pro missense NM_001407654.1:c.3967A>C NP_001394583.1:p.Thr1323Pro missense NM_001407655.1:c.3967A>C NP_001394584.1:p.Thr1323Pro missense NM_001407656.1:c.3967A>C NP_001394585.1:p.Thr1323Pro missense NM_001407657.1:c.3967A>C NP_001394586.1:p.Thr1323Pro missense NM_001407658.1:c.3967A>C NP_001394587.1:p.Thr1323Pro missense NM_001407659.1:c.3964A>C NP_001394588.1:p.Thr1322Pro missense NM_001407660.1:c.3964A>C NP_001394589.1:p.Thr1322Pro missense NM_001407661.1:c.3964A>C NP_001394590.1:p.Thr1322Pro missense NM_001407662.1:c.3964A>C NP_001394591.1:p.Thr1322Pro missense NM_001407663.1:c.3967A>C NP_001394592.1:p.Thr1323Pro missense NM_001407664.1:c.3922A>C NP_001394593.1:p.Thr1308Pro missense NM_001407665.1:c.3922A>C NP_001394594.1:p.Thr1308Pro missense NM_001407666.1:c.3922A>C NP_001394595.1:p.Thr1308Pro missense NM_001407667.1:c.3922A>C NP_001394596.1:p.Thr1308Pro missense NM_001407668.1:c.3922A>C NP_001394597.1:p.Thr1308Pro missense NM_001407669.1:c.3922A>C NP_001394598.1:p.Thr1308Pro missense NM_001407670.1:c.3919A>C NP_001394599.1:p.Thr1307Pro missense NM_001407671.1:c.3919A>C NP_001394600.1:p.Thr1307Pro missense NM_001407672.1:c.3919A>C NP_001394601.1:p.Thr1307Pro missense NM_001407673.1:c.3919A>C NP_001394602.1:p.Thr1307Pro missense NM_001407674.1:c.3922A>C NP_001394603.1:p.Thr1308Pro missense NM_001407675.1:c.3922A>C NP_001394604.1:p.Thr1308Pro missense NM_001407676.1:c.3922A>C NP_001394605.1:p.Thr1308Pro missense NM_001407677.1:c.3922A>C NP_001394606.1:p.Thr1308Pro missense NM_001407678.1:c.3922A>C NP_001394607.1:p.Thr1308Pro missense NM_001407679.1:c.3922A>C NP_001394608.1:p.Thr1308Pro missense NM_001407680.1:c.3922A>C NP_001394609.1:p.Thr1308Pro missense NM_001407681.1:c.3922A>C NP_001394610.1:p.Thr1308Pro missense NM_001407682.1:c.3922A>C NP_001394611.1:p.Thr1308Pro missense NM_001407683.1:c.3922A>C NP_001394612.1:p.Thr1308Pro missense NM_001407684.1:c.4045A>C NP_001394613.1:p.Thr1349Pro missense NM_001407685.1:c.3919A>C NP_001394614.1:p.Thr1307Pro missense NM_001407686.1:c.3919A>C NP_001394615.1:p.Thr1307Pro missense NM_001407687.1:c.3919A>C NP_001394616.1:p.Thr1307Pro missense NM_001407688.1:c.3919A>C NP_001394617.1:p.Thr1307Pro missense NM_001407689.1:c.3919A>C NP_001394618.1:p.Thr1307Pro missense NM_001407690.1:c.3919A>C NP_001394619.1:p.Thr1307Pro missense NM_001407691.1:c.3919A>C NP_001394620.1:p.Thr1307Pro missense NM_001407692.1:c.3904A>C NP_001394621.1:p.Thr1302Pro missense NM_001407694.1:c.3904A>C NP_001394623.1:p.Thr1302Pro missense NM_001407695.1:c.3904A>C NP_001394624.1:p.Thr1302Pro missense NM_001407696.1:c.3904A>C NP_001394625.1:p.Thr1302Pro missense NM_001407697.1:c.3904A>C NP_001394626.1:p.Thr1302Pro missense NM_001407698.1:c.3904A>C NP_001394627.1:p.Thr1302Pro missense NM_001407724.1:c.3904A>C NP_001394653.1:p.Thr1302Pro missense NM_001407725.1:c.3904A>C NP_001394654.1:p.Thr1302Pro missense NM_001407726.1:c.3904A>C NP_001394655.1:p.Thr1302Pro missense NM_001407727.1:c.3904A>C NP_001394656.1:p.Thr1302Pro missense NM_001407728.1:c.3904A>C NP_001394657.1:p.Thr1302Pro missense NM_001407729.1:c.3904A>C NP_001394658.1:p.Thr1302Pro missense NM_001407730.1:c.3904A>C NP_001394659.1:p.Thr1302Pro missense NM_001407731.1:c.3904A>C NP_001394660.1:p.Thr1302Pro missense NM_001407732.1:c.3904A>C NP_001394661.1:p.Thr1302Pro missense NM_001407733.1:c.3904A>C NP_001394662.1:p.Thr1302Pro missense NM_001407734.1:c.3904A>C NP_001394663.1:p.Thr1302Pro missense NM_001407735.1:c.3904A>C NP_001394664.1:p.Thr1302Pro missense NM_001407736.1:c.3904A>C NP_001394665.1:p.Thr1302Pro missense NM_001407737.1:c.3904A>C NP_001394666.1:p.Thr1302Pro missense NM_001407738.1:c.3904A>C NP_001394667.1:p.Thr1302Pro missense NM_001407739.1:c.3904A>C NP_001394668.1:p.Thr1302Pro missense NM_001407740.1:c.3901A>C NP_001394669.1:p.Thr1301Pro missense NM_001407741.1:c.3901A>C NP_001394670.1:p.Thr1301Pro missense NM_001407742.1:c.3901A>C NP_001394671.1:p.Thr1301Pro missense NM_001407743.1:c.3901A>C NP_001394672.1:p.Thr1301Pro missense NM_001407744.1:c.3901A>C NP_001394673.1:p.Thr1301Pro missense NM_001407745.1:c.3901A>C NP_001394674.1:p.Thr1301Pro missense NM_001407746.1:c.3901A>C NP_001394675.1:p.Thr1301Pro missense NM_001407747.1:c.3901A>C NP_001394676.1:p.Thr1301Pro missense NM_001407748.1:c.3901A>C NP_001394677.1:p.Thr1301Pro missense NM_001407749.1:c.3901A>C NP_001394678.1:p.Thr1301Pro missense NM_001407750.1:c.3904A>C NP_001394679.1:p.Thr1302Pro missense NM_001407751.1:c.3904A>C NP_001394680.1:p.Thr1302Pro missense NM_001407752.1:c.3904A>C NP_001394681.1:p.Thr1302Pro missense NM_001407838.1:c.3901A>C NP_001394767.1:p.Thr1301Pro missense NM_001407839.1:c.3901A>C NP_001394768.1:p.Thr1301Pro missense NM_001407841.1:c.3901A>C NP_001394770.1:p.Thr1301Pro missense NM_001407842.1:c.3901A>C NP_001394771.1:p.Thr1301Pro missense NM_001407843.1:c.3901A>C NP_001394772.1:p.Thr1301Pro missense NM_001407844.1:c.3901A>C NP_001394773.1:p.Thr1301Pro missense NM_001407845.1:c.3901A>C NP_001394774.1:p.Thr1301Pro missense NM_001407846.1:c.3901A>C NP_001394775.1:p.Thr1301Pro missense NM_001407847.1:c.3901A>C NP_001394776.1:p.Thr1301Pro missense NM_001407848.1:c.3901A>C NP_001394777.1:p.Thr1301Pro missense NM_001407849.1:c.3901A>C NP_001394778.1:p.Thr1301Pro missense NM_001407850.1:c.3904A>C NP_001394779.1:p.Thr1302Pro missense NM_001407851.1:c.3904A>C NP_001394780.1:p.Thr1302Pro missense NM_001407852.1:c.3904A>C NP_001394781.1:p.Thr1302Pro missense NM_001407853.1:c.3832A>C NP_001394782.1:p.Thr1278Pro missense NM_001407854.1:c.4045A>C NP_001394783.1:p.Thr1349Pro missense NM_001407858.1:c.4045A>C NP_001394787.1:p.Thr1349Pro missense NM_001407859.1:c.4045A>C NP_001394788.1:p.Thr1349Pro missense NM_001407860.1:c.4042A>C NP_001394789.1:p.Thr1348Pro missense NM_001407861.1:c.4042A>C NP_001394790.1:p.Thr1348Pro missense NM_001407862.1:c.3844A>C NP_001394791.1:p.Thr1282Pro missense NM_001407863.1:c.3922A>C NP_001394792.1:p.Thr1308Pro missense NM_001407874.1:c.3841A>C NP_001394803.1:p.Thr1281Pro missense NM_001407875.1:c.3841A>C NP_001394804.1:p.Thr1281Pro missense NM_001407879.1:c.3835A>C NP_001394808.1:p.Thr1279Pro missense NM_001407881.1:c.3835A>C NP_001394810.1:p.Thr1279Pro missense NM_001407882.1:c.3835A>C NP_001394811.1:p.Thr1279Pro missense NM_001407884.1:c.3835A>C NP_001394813.1:p.Thr1279Pro missense NM_001407885.1:c.3835A>C NP_001394814.1:p.Thr1279Pro missense NM_001407886.1:c.3835A>C NP_001394815.1:p.Thr1279Pro missense NM_001407887.1:c.3835A>C NP_001394816.1:p.Thr1279Pro missense NM_001407889.1:c.3835A>C NP_001394818.1:p.Thr1279Pro missense NM_001407894.1:c.3832A>C NP_001394823.1:p.Thr1278Pro missense NM_001407895.1:c.3832A>C NP_001394824.1:p.Thr1278Pro missense NM_001407896.1:c.3832A>C NP_001394825.1:p.Thr1278Pro missense NM_001407897.1:c.3832A>C NP_001394826.1:p.Thr1278Pro missense NM_001407898.1:c.3832A>C NP_001394827.1:p.Thr1278Pro missense NM_001407899.1:c.3832A>C NP_001394828.1:p.Thr1278Pro missense NM_001407900.1:c.3835A>C NP_001394829.1:p.Thr1279Pro missense NM_001407902.1:c.3835A>C NP_001394831.1:p.Thr1279Pro missense NM_001407904.1:c.3835A>C NP_001394833.1:p.Thr1279Pro missense NM_001407906.1:c.3835A>C NP_001394835.1:p.Thr1279Pro missense NM_001407907.1:c.3835A>C NP_001394836.1:p.Thr1279Pro missense NM_001407908.1:c.3835A>C NP_001394837.1:p.Thr1279Pro missense NM_001407909.1:c.3835A>C NP_001394838.1:p.Thr1279Pro missense NM_001407910.1:c.3835A>C NP_001394839.1:p.Thr1279Pro missense NM_001407915.1:c.3832A>C NP_001394844.1:p.Thr1278Pro missense NM_001407916.1:c.3832A>C NP_001394845.1:p.Thr1278Pro missense NM_001407917.1:c.3832A>C NP_001394846.1:p.Thr1278Pro missense NM_001407918.1:c.3832A>C NP_001394847.1:p.Thr1278Pro missense NM_001407919.1:c.3922A>C NP_001394848.1:p.Thr1308Pro missense NM_001407920.1:c.3781A>C NP_001394849.1:p.Thr1261Pro missense NM_001407921.1:c.3781A>C NP_001394850.1:p.Thr1261Pro missense NM_001407922.1:c.3781A>C NP_001394851.1:p.Thr1261Pro missense NM_001407923.1:c.3781A>C NP_001394852.1:p.Thr1261Pro missense NM_001407924.1:c.3781A>C NP_001394853.1:p.Thr1261Pro missense NM_001407925.1:c.3781A>C NP_001394854.1:p.Thr1261Pro missense NM_001407926.1:c.3781A>C NP_001394855.1:p.Thr1261Pro missense NM_001407927.1:c.3781A>C NP_001394856.1:p.Thr1261Pro missense NM_001407928.1:c.3781A>C NP_001394857.1:p.Thr1261Pro missense NM_001407929.1:c.3781A>C NP_001394858.1:p.Thr1261Pro missense NM_001407930.1:c.3778A>C NP_001394859.1:p.Thr1260Pro missense NM_001407931.1:c.3778A>C NP_001394860.1:p.Thr1260Pro missense NM_001407932.1:c.3778A>C NP_001394861.1:p.Thr1260Pro missense NM_001407933.1:c.3781A>C NP_001394862.1:p.Thr1261Pro missense NM_001407934.1:c.3778A>C NP_001394863.1:p.Thr1260Pro missense NM_001407935.1:c.3781A>C NP_001394864.1:p.Thr1261Pro missense NM_001407936.1:c.3778A>C NP_001394865.1:p.Thr1260Pro missense NM_001407937.1:c.3922A>C NP_001394866.1:p.Thr1308Pro missense NM_001407938.1:c.3922A>C NP_001394867.1:p.Thr1308Pro missense NM_001407939.1:c.3922A>C NP_001394868.1:p.Thr1308Pro missense NM_001407940.1:c.3919A>C NP_001394869.1:p.Thr1307Pro missense NM_001407941.1:c.3919A>C NP_001394870.1:p.Thr1307Pro missense NM_001407942.1:c.3904A>C NP_001394871.1:p.Thr1302Pro missense NM_001407943.1:c.3901A>C NP_001394872.1:p.Thr1301Pro missense NM_001407944.1:c.3904A>C NP_001394873.1:p.Thr1302Pro missense NM_001407945.1:c.3904A>C NP_001394874.1:p.Thr1302Pro missense NM_001407946.1:c.3712A>C NP_001394875.1:p.Thr1238Pro missense NM_001407947.1:c.3712A>C NP_001394876.1:p.Thr1238Pro missense NM_001407948.1:c.3712A>C NP_001394877.1:p.Thr1238Pro missense NM_001407949.1:c.3712A>C NP_001394878.1:p.Thr1238Pro missense NM_001407950.1:c.3712A>C NP_001394879.1:p.Thr1238Pro missense NM_001407951.1:c.3712A>C NP_001394880.1:p.Thr1238Pro missense NM_001407952.1:c.3712A>C NP_001394881.1:p.Thr1238Pro missense NM_001407953.1:c.3712A>C NP_001394882.1:p.Thr1238Pro missense NM_001407954.1:c.3709A>C NP_001394883.1:p.Thr1237Pro missense NM_001407955.1:c.3709A>C NP_001394884.1:p.Thr1237Pro missense NM_001407956.1:c.3709A>C NP_001394885.1:p.Thr1237Pro missense NM_001407957.1:c.3712A>C NP_001394886.1:p.Thr1238Pro missense NM_001407958.1:c.3709A>C NP_001394887.1:p.Thr1237Pro missense NM_001407959.1:c.3664A>C NP_001394888.1:p.Thr1222Pro missense NM_001407960.1:c.3664A>C NP_001394889.1:p.Thr1222Pro missense NM_001407962.1:c.3661A>C NP_001394891.1:p.Thr1221Pro missense NM_001407963.1:c.3664A>C NP_001394892.1:p.Thr1222Pro missense NM_001407964.1:c.3901A>C NP_001394893.1:p.Thr1301Pro missense NM_001407965.1:c.3541A>C NP_001394894.1:p.Thr1181Pro missense NM_001407966.1:c.3157A>C NP_001394895.1:p.Thr1053Pro missense NM_001407967.1:c.3157A>C NP_001394896.1:p.Thr1053Pro missense NM_001407968.1:c.1441A>C NP_001394897.1:p.Thr481Pro missense NM_001407969.1:c.1441A>C NP_001394898.1:p.Thr481Pro missense NM_001407970.1:c.788-454A>C intron variant NM_001407971.1:c.788-454A>C intron variant NM_001407972.1:c.785-454A>C intron variant NM_001407973.1:c.788-454A>C intron variant NM_001407974.1:c.788-454A>C intron variant NM_001407975.1:c.788-454A>C intron variant NM_001407976.1:c.788-454A>C intron variant NM_001407977.1:c.788-454A>C intron variant NM_001407978.1:c.788-454A>C intron variant NM_001407979.1:c.788-454A>C intron variant NM_001407980.1:c.788-454A>C intron variant NM_001407981.1:c.788-454A>C intron variant NM_001407982.1:c.788-454A>C intron variant NM_001407983.1:c.788-454A>C intron variant NM_001407984.1:c.785-454A>C intron variant NM_001407985.1:c.785-454A>C intron variant NM_001407986.1:c.785-454A>C intron variant NM_001407990.1:c.788-454A>C intron variant NM_001407991.1:c.785-454A>C intron variant NM_001407992.1:c.785-454A>C intron variant NM_001407993.1:c.788-454A>C intron variant NM_001408392.1:c.785-454A>C intron variant NM_001408396.1:c.785-454A>C intron variant NM_001408397.1:c.785-454A>C intron variant NM_001408398.1:c.785-454A>C intron variant NM_001408399.1:c.785-454A>C intron variant NM_001408400.1:c.785-454A>C intron variant NM_001408401.1:c.785-454A>C intron variant NM_001408402.1:c.785-454A>C intron variant NM_001408403.1:c.788-454A>C intron variant NM_001408404.1:c.788-454A>C intron variant NM_001408406.1:c.791-463A>C intron variant NM_001408407.1:c.785-454A>C intron variant NM_001408408.1:c.779-454A>C intron variant NM_001408409.1:c.710-454A>C intron variant NM_001408410.1:c.647-454A>C intron variant NM_001408411.1:c.710-454A>C intron variant NM_001408412.1:c.710-454A>C intron variant NM_001408413.1:c.707-454A>C intron variant NM_001408414.1:c.710-454A>C intron variant NM_001408415.1:c.710-454A>C intron variant NM_001408416.1:c.707-454A>C intron variant NM_001408418.1:c.671-454A>C intron variant NM_001408419.1:c.671-454A>C intron variant NM_001408420.1:c.671-454A>C intron variant NM_001408421.1:c.668-454A>C intron variant NM_001408422.1:c.671-454A>C intron variant NM_001408423.1:c.671-454A>C intron variant NM_001408424.1:c.668-454A>C intron variant NM_001408425.1:c.665-454A>C intron variant NM_001408426.1:c.665-454A>C intron variant NM_001408427.1:c.665-454A>C intron variant NM_001408428.1:c.665-454A>C intron variant NM_001408429.1:c.665-454A>C intron variant NM_001408430.1:c.665-454A>C intron variant NM_001408431.1:c.668-454A>C intron variant NM_001408432.1:c.662-454A>C intron variant NM_001408433.1:c.662-454A>C intron variant NM_001408434.1:c.662-454A>C intron variant NM_001408435.1:c.662-454A>C intron variant NM_001408436.1:c.665-454A>C intron variant NM_001408437.1:c.665-454A>C intron variant NM_001408438.1:c.665-454A>C intron variant NM_001408439.1:c.665-454A>C intron variant NM_001408440.1:c.665-454A>C intron variant NM_001408441.1:c.665-454A>C intron variant NM_001408442.1:c.665-454A>C intron variant NM_001408443.1:c.665-454A>C intron variant NM_001408444.1:c.665-454A>C intron variant NM_001408445.1:c.662-454A>C intron variant NM_001408446.1:c.662-454A>C intron variant NM_001408447.1:c.662-454A>C intron variant NM_001408448.1:c.662-454A>C intron variant NM_001408450.1:c.662-454A>C intron variant NM_001408451.1:c.653-454A>C intron variant NM_001408452.1:c.647-454A>C intron variant NM_001408453.1:c.647-454A>C intron variant NM_001408454.1:c.647-454A>C intron variant NM_001408455.1:c.647-454A>C intron variant NM_001408456.1:c.647-454A>C intron variant NM_001408457.1:c.647-454A>C intron variant NM_001408458.1:c.647-454A>C intron variant NM_001408459.1:c.647-454A>C intron variant NM_001408460.1:c.647-454A>C intron variant NM_001408461.1:c.647-454A>C intron variant NM_001408462.1:c.644-454A>C intron variant NM_001408463.1:c.644-454A>C intron variant NM_001408464.1:c.644-454A>C intron variant NM_001408465.1:c.644-454A>C intron variant NM_001408466.1:c.647-454A>C intron variant NM_001408467.1:c.647-454A>C intron variant NM_001408468.1:c.644-454A>C intron variant NM_001408469.1:c.647-454A>C intron variant NM_001408470.1:c.644-454A>C intron variant NM_001408472.1:c.788-454A>C intron variant NM_001408473.1:c.785-454A>C intron variant NM_001408474.1:c.587-454A>C intron variant NM_001408475.1:c.584-454A>C intron variant NM_001408476.1:c.587-454A>C intron variant NM_001408478.1:c.578-454A>C intron variant NM_001408479.1:c.578-454A>C intron variant NM_001408480.1:c.578-454A>C intron variant NM_001408481.1:c.578-454A>C intron variant NM_001408482.1:c.578-454A>C intron variant NM_001408483.1:c.578-454A>C intron variant NM_001408484.1:c.578-454A>C intron variant NM_001408485.1:c.578-454A>C intron variant NM_001408489.1:c.578-454A>C intron variant NM_001408490.1:c.575-454A>C intron variant NM_001408491.1:c.575-454A>C intron variant NM_001408492.1:c.578-454A>C intron variant NM_001408493.1:c.575-454A>C intron variant NM_001408494.1:c.548-454A>C intron variant NM_001408495.1:c.545-454A>C intron variant NM_001408496.1:c.524-454A>C intron variant NM_001408497.1:c.524-454A>C intron variant NM_001408498.1:c.524-454A>C intron variant NM_001408499.1:c.524-454A>C intron variant NM_001408500.1:c.524-454A>C intron variant NM_001408501.1:c.524-454A>C intron variant NM_001408502.1:c.455-454A>C intron variant NM_001408503.1:c.521-454A>C intron variant NM_001408504.1:c.521-454A>C intron variant NM_001408505.1:c.521-454A>C intron variant NM_001408506.1:c.461-454A>C intron variant NM_001408507.1:c.461-454A>C intron variant NM_001408508.1:c.452-454A>C intron variant NM_001408509.1:c.452-454A>C intron variant NM_001408510.1:c.407-454A>C intron variant NM_001408511.1:c.404-454A>C intron variant NM_001408512.1:c.284-454A>C intron variant NM_001408513.1:c.578-454A>C intron variant NM_001408514.1:c.578-454A>C intron variant NM_007297.4:c.3904A>C NP_009228.2:p.Thr1302Pro missense NM_007298.4:c.788-454A>C intron variant NM_007299.4:c.788-454A>C intron variant NM_007300.4:c.4045A>C NP_009231.2:p.Thr1349Pro missense NR_027676.1:n.4181A>C NC_000017.11:g.43091486T>G NC_000017.10:g.41243503T>G NG_005905.2:g.126498A>C NG_087068.1:g.468T>G LRG_292:g.126498A>C LRG_292t1:c.4045A>C LRG_292p1:p.Thr1349Pro U14680.1:n.4164A>C - Protein change
- T1349P, T1302P, T1221P, T1278P, T1307P, T1322P, T1053P, T1222P, T1237P, T1282P, T1346P, T481P, T1181P, T1238P, T1279P, T1308P, T1323P, T1260P, T1261P, T1281P, T1301P, T1348P
- Other names
- -
- Canonical SPDI
- NC_000017.11:43091485:T:G
-
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.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13044 | 14850 | |
| LOC126862571 | - | - | - | GRCh38 | - | 1651 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, single submitter
|
Aug 28, 2023 | RCV000112232.5 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Aug 3, 2023 | RCV001021741.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 18, 2023 | RCV001359626.8 |
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
(Aug 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004817718.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces threonine with proline at codon 1349 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with proline at codon 1349 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer case-control meta-analysis in 1/60465 cases and 1/53460 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000286). This variant has been identified in 5/282502 chromosomes 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: 2
|
|
|
Uncertain significance
(Aug 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001183392.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.T1349P variant (also known as c.4045A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide … (more)
The p.T1349P variant (also known as c.4045A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 4045. The threonine at codon 1349 is replaced by proline, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094; Yao L et al. J Hum Genet, 2022 Nov;67:639-642). This amino acid position is not well conserved in available vertebrate species, and proline is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Likely benign
(Mar 23, 2023)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV003850359.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Comment:
BRCA1 coldspot (exon 11 using historical exon numbering). Reclassification based on statistical prior probability
|
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
|
|
|
Uncertain significance
(Apr 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004360200.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with proline at codon 1349 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with proline at codon 1349 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000286). This variant has been identified in 5/282502 chromosomes 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)
|
|
|
Uncertain significance
(May 18, 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: SCV001555501.4
First in ClinVar: Apr 13, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1349 of the BRCA1 protein (p.Thr1349Pro). … (more)
This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1349 of the BRCA1 protein (p.Thr1349Pro). This variant is present in population databases (rs80357231, gnomAD 0.02%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 55084). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. (less)
|
|
|
Uncertain significance
(Apr 05, 1999)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000144945.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
|
Comment:
Comment:
The p.T1349P variant (also known as c.4045A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 4045. The threonine at codon 1349 is replaced by proline, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094; Yao L et al. J Hum Genet, 2022 Nov;67:639-642). This amino acid position is not well conserved in available vertebrate species, and proline is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Comment:
This missense variant replaces threonine with proline at codon 1349 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000286). This variant has been identified in 5/282502 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1349 of the BRCA1 protein (p.Thr1349Pro). This variant is present in population databases (rs80357231, gnomAD 0.02%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 55084). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions.
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 missense variant replaces threonine with proline at codon 1349 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer case-control meta-analysis in 1/60465 cases and 1/53460 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000286). This variant has been identified in 5/282502 chromosomes 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.T1349P variant (also known as c.4045A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 4045. The threonine at codon 1349 is replaced by proline, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094; Yao L et al. J Hum Genet, 2022 Nov;67:639-642). This amino acid position is not well conserved in available vertebrate species, and proline is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Comment:
This missense variant replaces threonine with proline at codon 1349 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000286). This variant has been identified in 5/282502 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1349 of the BRCA1 protein (p.Thr1349Pro). This variant is present in population databases (rs80357231, gnomAD 0.02%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 55084). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Ovarian cancer risk of Chinese women with BRCA1/2 germline pathogenic variants. | Yao L | Journal of human genetics | 2022 | PMID: 35864222 |
| Rates of Variants of Uncertain Significance Among Patients With Breast Cancer Undergoing Genetic Testing: Regional Perspectives. | Abdel-Razeq H | Frontiers in oncology | 2022 | PMID: 35402282 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". | Dines JN | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31911673 |
| Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. | Abkevich V | Journal of medical genetics | 2004 | PMID: 15235020 |
Text-mined citations for rs80357231 ...
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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.