IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000321
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5531T>G (p.Leu1844Arg)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Benign
Jun 2019 by
Evidence-based…
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.5531T>G (p.Leu1844Arg)
Variation ID: 55615 Accession: VCV000055615.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43045739 (GRCh38) [ NCBI UCSC ] 17: 41197756 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 29, 2024 Jun 18, 2019 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.5531T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Leu1844Arg missense NM_001407571.1:c.5318T>G NP_001394500.1:p.Leu1773Arg missense NM_001407581.1:c.5597T>G NP_001394510.1:p.Leu1866Arg missense NM_001407582.1:c.5597T>G NP_001394511.1:p.Leu1866Arg missense NM_001407583.1:c.5594T>G NP_001394512.1:p.Leu1865Arg missense NM_001407585.1:c.5594T>G NP_001394514.1:p.Leu1865Arg missense NM_001407587.1:c.5594T>G NP_001394516.1:p.Leu1865Arg missense NM_001407590.1:c.5591T>G NP_001394519.1:p.Leu1864Arg missense NM_001407591.1:c.5591T>G NP_001394520.1:p.Leu1864Arg missense NM_001407593.1:c.5531T>G NP_001394522.1:p.Leu1844Arg missense NM_001407594.1:c.5531T>G NP_001394523.1:p.Leu1844Arg missense NM_001407596.1:c.5531T>G NP_001394525.1:p.Leu1844Arg missense NM_001407597.1:c.5531T>G NP_001394526.1:p.Leu1844Arg missense NM_001407598.1:c.5531T>G NP_001394527.1:p.Leu1844Arg missense NM_001407602.1:c.5531T>G NP_001394531.1:p.Leu1844Arg missense NM_001407603.1:c.5531T>G NP_001394532.1:p.Leu1844Arg missense NM_001407605.1:c.5531T>G NP_001394534.1:p.Leu1844Arg missense NM_001407610.1:c.5528T>G NP_001394539.1:p.Leu1843Arg missense NM_001407611.1:c.5528T>G NP_001394540.1:p.Leu1843Arg missense NM_001407612.1:c.5528T>G NP_001394541.1:p.Leu1843Arg missense NM_001407613.1:c.5528T>G NP_001394542.1:p.Leu1843Arg missense NM_001407614.1:c.5528T>G NP_001394543.1:p.Leu1843Arg missense NM_001407615.1:c.5528T>G NP_001394544.1:p.Leu1843Arg missense NM_001407616.1:c.5528T>G NP_001394545.1:p.Leu1843Arg missense NM_001407617.1:c.5528T>G NP_001394546.1:p.Leu1843Arg missense NM_001407618.1:c.5528T>G NP_001394547.1:p.Leu1843Arg missense NM_001407619.1:c.5528T>G NP_001394548.1:p.Leu1843Arg missense NM_001407620.1:c.5528T>G NP_001394549.1:p.Leu1843Arg missense NM_001407621.1:c.5528T>G NP_001394550.1:p.Leu1843Arg missense NM_001407622.1:c.5528T>G NP_001394551.1:p.Leu1843Arg missense NM_001407623.1:c.5528T>G NP_001394552.1:p.Leu1843Arg missense NM_001407624.1:c.5528T>G NP_001394553.1:p.Leu1843Arg missense NM_001407625.1:c.5528T>G NP_001394554.1:p.Leu1843Arg missense NM_001407626.1:c.5528T>G NP_001394555.1:p.Leu1843Arg missense NM_001407627.1:c.5525T>G NP_001394556.1:p.Leu1842Arg missense NM_001407628.1:c.5525T>G NP_001394557.1:p.Leu1842Arg missense NM_001407629.1:c.5525T>G NP_001394558.1:p.Leu1842Arg missense NM_001407630.1:c.5525T>G NP_001394559.1:p.Leu1842Arg missense NM_001407631.1:c.5525T>G NP_001394560.1:p.Leu1842Arg missense NM_001407632.1:c.5525T>G NP_001394561.1:p.Leu1842Arg missense NM_001407633.1:c.5525T>G NP_001394562.1:p.Leu1842Arg missense NM_001407634.1:c.5525T>G NP_001394563.1:p.Leu1842Arg missense NM_001407635.1:c.5525T>G NP_001394564.1:p.Leu1842Arg missense NM_001407636.1:c.5525T>G NP_001394565.1:p.Leu1842Arg missense NM_001407637.1:c.5525T>G NP_001394566.1:p.Leu1842Arg missense NM_001407638.1:c.5525T>G NP_001394567.1:p.Leu1842Arg missense NM_001407639.1:c.5525T>G NP_001394568.1:p.Leu1842Arg missense NM_001407640.1:c.5525T>G NP_001394569.1:p.Leu1842Arg missense NM_001407641.1:c.5525T>G NP_001394570.1:p.Leu1842Arg missense NM_001407642.1:c.5525T>G NP_001394571.1:p.Leu1842Arg missense NM_001407644.1:c.5522T>G NP_001394573.1:p.Leu1841Arg missense NM_001407645.1:c.5522T>G NP_001394574.1:p.Leu1841Arg missense NM_001407646.1:c.5519T>G NP_001394575.1:p.Leu1840Arg missense NM_001407647.1:c.5516T>G NP_001394576.1:p.Leu1839Arg missense NM_001407648.1:c.5474T>G NP_001394577.1:p.Leu1825Arg missense NM_001407649.1:c.5471T>G NP_001394578.1:p.Leu1824Arg missense NM_001407652.1:c.5453T>G NP_001394581.1:p.Leu1818Arg missense NM_001407653.1:c.5453T>G NP_001394582.1:p.Leu1818Arg missense NM_001407654.1:c.5453T>G NP_001394583.1:p.Leu1818Arg missense NM_001407655.1:c.5453T>G NP_001394584.1:p.Leu1818Arg missense NM_001407656.1:c.5450T>G NP_001394585.1:p.Leu1817Arg missense NM_001407657.1:c.5450T>G NP_001394586.1:p.Leu1817Arg missense NM_001407658.1:c.5450T>G NP_001394587.1:p.Leu1817Arg missense NM_001407659.1:c.5447T>G NP_001394588.1:p.Leu1816Arg missense NM_001407660.1:c.5447T>G NP_001394589.1:p.Leu1816Arg missense NM_001407661.1:c.5447T>G NP_001394590.1:p.Leu1816Arg missense NM_001407662.1:c.5447T>G NP_001394591.1:p.Leu1816Arg missense NM_001407663.1:c.5447T>G NP_001394592.1:p.Leu1816Arg missense NM_001407664.1:c.5408T>G NP_001394593.1:p.Leu1803Arg missense NM_001407665.1:c.5408T>G NP_001394594.1:p.Leu1803Arg missense NM_001407666.1:c.5408T>G NP_001394595.1:p.Leu1803Arg missense NM_001407667.1:c.5408T>G NP_001394596.1:p.Leu1803Arg missense NM_001407668.1:c.5408T>G NP_001394597.1:p.Leu1803Arg missense NM_001407669.1:c.5408T>G NP_001394598.1:p.Leu1803Arg missense NM_001407670.1:c.5405T>G NP_001394599.1:p.Leu1802Arg missense NM_001407671.1:c.5405T>G NP_001394600.1:p.Leu1802Arg missense NM_001407672.1:c.5405T>G NP_001394601.1:p.Leu1802Arg missense NM_001407673.1:c.5405T>G NP_001394602.1:p.Leu1802Arg missense NM_001407674.1:c.5405T>G NP_001394603.1:p.Leu1802Arg missense NM_001407675.1:c.5405T>G NP_001394604.1:p.Leu1802Arg missense NM_001407676.1:c.5405T>G NP_001394605.1:p.Leu1802Arg missense NM_001407677.1:c.5405T>G NP_001394606.1:p.Leu1802Arg missense NM_001407678.1:c.5405T>G NP_001394607.1:p.Leu1802Arg missense NM_001407679.1:c.5405T>G NP_001394608.1:p.Leu1802Arg missense NM_001407680.1:c.5405T>G NP_001394609.1:p.Leu1802Arg missense NM_001407681.1:c.5402T>G NP_001394610.1:p.Leu1801Arg missense NM_001407682.1:c.5402T>G NP_001394611.1:p.Leu1801Arg missense NM_001407683.1:c.5402T>G NP_001394612.1:p.Leu1801Arg missense NM_001407684.1:c.5402T>G NP_001394613.1:p.Leu1801Arg missense NM_001407685.1:c.5402T>G NP_001394614.1:p.Leu1801Arg missense NM_001407686.1:c.5402T>G NP_001394615.1:p.Leu1801Arg missense NM_001407687.1:c.5402T>G NP_001394616.1:p.Leu1801Arg missense NM_001407688.1:c.5402T>G NP_001394617.1:p.Leu1801Arg missense NM_001407689.1:c.5402T>G NP_001394618.1:p.Leu1801Arg missense NM_001407690.1:c.5399T>G NP_001394619.1:p.Leu1800Arg missense NM_001407691.1:c.5399T>G NP_001394620.1:p.Leu1800Arg missense NM_001407692.1:c.5390T>G NP_001394621.1:p.Leu1797Arg missense NM_001407694.1:c.5390T>G NP_001394623.1:p.Leu1797Arg missense NM_001407695.1:c.5390T>G NP_001394624.1:p.Leu1797Arg missense NM_001407696.1:c.5390T>G NP_001394625.1:p.Leu1797Arg missense NM_001407697.1:c.5390T>G NP_001394626.1:p.Leu1797Arg missense NM_001407698.1:c.5390T>G NP_001394627.1:p.Leu1797Arg missense NM_001407724.1:c.5390T>G NP_001394653.1:p.Leu1797Arg missense NM_001407725.1:c.5390T>G NP_001394654.1:p.Leu1797Arg missense NM_001407726.1:c.5390T>G NP_001394655.1:p.Leu1797Arg missense NM_001407727.1:c.5390T>G NP_001394656.1:p.Leu1797Arg missense NM_001407728.1:c.5390T>G NP_001394657.1:p.Leu1797Arg missense NM_001407729.1:c.5390T>G NP_001394658.1:p.Leu1797Arg missense NM_001407730.1:c.5390T>G NP_001394659.1:p.Leu1797Arg missense NM_001407731.1:c.5390T>G NP_001394660.1:p.Leu1797Arg missense NM_001407732.1:c.5387T>G NP_001394661.1:p.Leu1796Arg missense NM_001407733.1:c.5387T>G NP_001394662.1:p.Leu1796Arg missense NM_001407734.1:c.5387T>G NP_001394663.1:p.Leu1796Arg missense NM_001407735.1:c.5387T>G NP_001394664.1:p.Leu1796Arg missense NM_001407736.1:c.5387T>G NP_001394665.1:p.Leu1796Arg missense NM_001407737.1:c.5387T>G NP_001394666.1:p.Leu1796Arg missense NM_001407738.1:c.5387T>G NP_001394667.1:p.Leu1796Arg missense NM_001407739.1:c.5387T>G NP_001394668.1:p.Leu1796Arg missense NM_001407740.1:c.5387T>G NP_001394669.1:p.Leu1796Arg missense NM_001407741.1:c.5387T>G NP_001394670.1:p.Leu1796Arg missense NM_001407742.1:c.5387T>G NP_001394671.1:p.Leu1796Arg missense NM_001407743.1:c.5387T>G NP_001394672.1:p.Leu1796Arg missense NM_001407744.1:c.5387T>G NP_001394673.1:p.Leu1796Arg missense NM_001407745.1:c.5387T>G NP_001394674.1:p.Leu1796Arg missense NM_001407746.1:c.5387T>G NP_001394675.1:p.Leu1796Arg missense NM_001407747.1:c.5387T>G NP_001394676.1:p.Leu1796Arg missense NM_001407748.1:c.5387T>G NP_001394677.1:p.Leu1796Arg missense NM_001407749.1:c.5387T>G NP_001394678.1:p.Leu1796Arg missense NM_001407750.1:c.5387T>G NP_001394679.1:p.Leu1796Arg missense NM_001407751.1:c.5387T>G NP_001394680.1:p.Leu1796Arg missense NM_001407752.1:c.5387T>G NP_001394681.1:p.Leu1796Arg missense NM_001407838.1:c.5384T>G NP_001394767.1:p.Leu1795Arg missense NM_001407839.1:c.5384T>G NP_001394768.1:p.Leu1795Arg missense NM_001407841.1:c.5384T>G NP_001394770.1:p.Leu1795Arg missense NM_001407842.1:c.5384T>G NP_001394771.1:p.Leu1795Arg missense NM_001407843.1:c.5384T>G NP_001394772.1:p.Leu1795Arg missense NM_001407844.1:c.5384T>G NP_001394773.1:p.Leu1795Arg missense NM_001407845.1:c.5384T>G NP_001394774.1:p.Leu1795Arg missense NM_001407846.1:c.5384T>G NP_001394775.1:p.Leu1795Arg missense NM_001407847.1:c.5384T>G NP_001394776.1:p.Leu1795Arg missense NM_001407848.1:c.5384T>G NP_001394777.1:p.Leu1795Arg missense NM_001407849.1:c.5384T>G NP_001394778.1:p.Leu1795Arg missense NM_001407850.1:c.5384T>G NP_001394779.1:p.Leu1795Arg missense NM_001407851.1:c.5384T>G NP_001394780.1:p.Leu1795Arg missense NM_001407852.1:c.5384T>G NP_001394781.1:p.Leu1795Arg missense NM_001407853.1:c.5384T>G NP_001394782.1:p.Leu1795Arg missense NM_001407854.1:c.*45T>G NM_001407858.1:c.*45T>G NM_001407859.1:c.*45T>G NM_001407860.1:c.*45T>G NM_001407861.1:c.*45T>G NM_001407862.1:c.5330T>G NP_001394791.1:p.Leu1777Arg missense NM_001407863.1:c.5327T>G NP_001394792.1:p.Leu1776Arg missense NM_001407874.1:c.5324T>G NP_001394803.1:p.Leu1775Arg missense NM_001407875.1:c.5324T>G NP_001394804.1:p.Leu1775Arg missense NM_001407879.1:c.5321T>G NP_001394808.1:p.Leu1774Arg missense NM_001407881.1:c.5321T>G NP_001394810.1:p.Leu1774Arg missense NM_001407882.1:c.5321T>G NP_001394811.1:p.Leu1774Arg missense NM_001407884.1:c.5321T>G NP_001394813.1:p.Leu1774Arg missense NM_001407885.1:c.5321T>G NP_001394814.1:p.Leu1774Arg missense NM_001407886.1:c.5321T>G NP_001394815.1:p.Leu1774Arg missense NM_001407887.1:c.5321T>G NP_001394816.1:p.Leu1774Arg missense NM_001407889.1:c.5321T>G NP_001394818.1:p.Leu1774Arg missense NM_001407894.1:c.5318T>G NP_001394823.1:p.Leu1773Arg missense NM_001407895.1:c.5318T>G NP_001394824.1:p.Leu1773Arg missense NM_001407896.1:c.5318T>G NP_001394825.1:p.Leu1773Arg missense NM_001407897.1:c.5318T>G NP_001394826.1:p.Leu1773Arg missense NM_001407898.1:c.5318T>G NP_001394827.1:p.Leu1773Arg missense NM_001407899.1:c.5318T>G NP_001394828.1:p.Leu1773Arg missense NM_001407900.1:c.5318T>G NP_001394829.1:p.Leu1773Arg missense NM_001407902.1:c.5318T>G NP_001394831.1:p.Leu1773Arg missense NM_001407904.1:c.5318T>G NP_001394833.1:p.Leu1773Arg missense NM_001407906.1:c.5318T>G NP_001394835.1:p.Leu1773Arg missense NM_001407907.1:c.5318T>G NP_001394836.1:p.Leu1773Arg missense NM_001407908.1:c.5318T>G NP_001394837.1:p.Leu1773Arg missense NM_001407909.1:c.5318T>G NP_001394838.1:p.Leu1773Arg missense NM_001407910.1:c.5318T>G NP_001394839.1:p.Leu1773Arg missense NM_001407915.1:c.5315T>G NP_001394844.1:p.Leu1772Arg missense NM_001407916.1:c.5315T>G NP_001394845.1:p.Leu1772Arg missense NM_001407917.1:c.5315T>G NP_001394846.1:p.Leu1772Arg missense NM_001407918.1:c.5315T>G NP_001394847.1:p.Leu1772Arg missense NM_001407919.1:c.5279T>G NP_001394848.1:p.Leu1760Arg missense NM_001407920.1:c.5267T>G NP_001394849.1:p.Leu1756Arg missense NM_001407921.1:c.5267T>G NP_001394850.1:p.Leu1756Arg missense NM_001407922.1:c.5267T>G NP_001394851.1:p.Leu1756Arg missense NM_001407923.1:c.5267T>G NP_001394852.1:p.Leu1756Arg missense NM_001407924.1:c.5267T>G NP_001394853.1:p.Leu1756Arg missense NM_001407925.1:c.5267T>G NP_001394854.1:p.Leu1756Arg missense NM_001407926.1:c.5267T>G NP_001394855.1:p.Leu1756Arg missense NM_001407927.1:c.5264T>G NP_001394856.1:p.Leu1755Arg missense NM_001407928.1:c.5264T>G NP_001394857.1:p.Leu1755Arg missense NM_001407929.1:c.5264T>G NP_001394858.1:p.Leu1755Arg missense NM_001407930.1:c.5264T>G NP_001394859.1:p.Leu1755Arg missense NM_001407931.1:c.5264T>G NP_001394860.1:p.Leu1755Arg missense NM_001407932.1:c.5264T>G NP_001394861.1:p.Leu1755Arg missense NM_001407933.1:c.5264T>G NP_001394862.1:p.Leu1755Arg missense NM_001407934.1:c.5261T>G NP_001394863.1:p.Leu1754Arg missense NM_001407935.1:c.5261T>G NP_001394864.1:p.Leu1754Arg missense NM_001407936.1:c.5261T>G NP_001394865.1:p.Leu1754Arg missense NM_001407937.1:c.*45T>G NM_001407938.1:c.*45T>G NM_001407939.1:c.*45T>G NM_001407940.1:c.*45T>G NM_001407941.1:c.*45T>G NM_001407942.1:c.*45T>G NM_001407943.1:c.*45T>G NM_001407944.1:c.*45T>G NM_001407945.1:c.*45T>G NM_001407946.1:c.5198T>G NP_001394875.1:p.Leu1733Arg missense NM_001407947.1:c.5198T>G NP_001394876.1:p.Leu1733Arg missense NM_001407948.1:c.5198T>G NP_001394877.1:p.Leu1733Arg missense NM_001407949.1:c.5198T>G NP_001394878.1:p.Leu1733Arg missense NM_001407950.1:c.5195T>G NP_001394879.1:p.Leu1732Arg missense NM_001407951.1:c.5195T>G NP_001394880.1:p.Leu1732Arg missense NM_001407952.1:c.5195T>G NP_001394881.1:p.Leu1732Arg missense NM_001407953.1:c.5195T>G NP_001394882.1:p.Leu1732Arg missense NM_001407954.1:c.5195T>G NP_001394883.1:p.Leu1732Arg missense NM_001407955.1:c.5195T>G NP_001394884.1:p.Leu1732Arg missense NM_001407956.1:c.5192T>G NP_001394885.1:p.Leu1731Arg missense NM_001407957.1:c.5192T>G NP_001394886.1:p.Leu1731Arg missense NM_001407958.1:c.5192T>G NP_001394887.1:p.Leu1731Arg missense NM_001407959.1:c.5150T>G NP_001394888.1:p.Leu1717Arg missense NM_001407960.1:c.5147T>G NP_001394889.1:p.Leu1716Arg missense NM_001407962.1:c.5147T>G NP_001394891.1:p.Leu1716Arg missense NM_001407963.1:c.5144T>G NP_001394892.1:p.Leu1715Arg missense NM_001407964.1:c.5069T>G NP_001394893.1:p.Leu1690Arg missense NM_001407965.1:c.5024T>G NP_001394894.1:p.Leu1675Arg missense NM_001407966.1:c.4643T>G NP_001394895.1:p.Leu1548Arg missense NM_001407967.1:c.4640T>G NP_001394896.1:p.Leu1547Arg missense NM_001407968.1:c.2927T>G NP_001394897.1:p.Leu976Arg missense NM_001407969.1:c.2924T>G NP_001394898.1:p.Leu975Arg missense NM_001407970.1:c.2288T>G NP_001394899.1:p.Leu763Arg missense NM_001407971.1:c.2288T>G NP_001394900.1:p.Leu763Arg missense NM_001407972.1:c.2285T>G NP_001394901.1:p.Leu762Arg missense NM_001407973.1:c.2222T>G NP_001394902.1:p.Leu741Arg missense NM_001407974.1:c.2222T>G NP_001394903.1:p.Leu741Arg missense NM_001407975.1:c.2222T>G NP_001394904.1:p.Leu741Arg missense NM_001407976.1:c.2222T>G NP_001394905.1:p.Leu741Arg missense NM_001407977.1:c.2222T>G NP_001394906.1:p.Leu741Arg missense NM_001407978.1:c.2222T>G NP_001394907.1:p.Leu741Arg missense NM_001407979.1:c.2219T>G NP_001394908.1:p.Leu740Arg missense NM_001407980.1:c.2219T>G NP_001394909.1:p.Leu740Arg missense NM_001407981.1:c.2219T>G NP_001394910.1:p.Leu740Arg missense NM_001407982.1:c.2219T>G NP_001394911.1:p.Leu740Arg missense NM_001407983.1:c.2219T>G NP_001394912.1:p.Leu740Arg missense NM_001407984.1:c.2219T>G NP_001394913.1:p.Leu740Arg missense NM_001407985.1:c.2219T>G NP_001394914.1:p.Leu740Arg missense NM_001407986.1:c.2219T>G NP_001394915.1:p.Leu740Arg missense NM_001407990.1:c.2219T>G NP_001394919.1:p.Leu740Arg missense NM_001407991.1:c.2219T>G NP_001394920.1:p.Leu740Arg missense NM_001407992.1:c.2219T>G NP_001394921.1:p.Leu740Arg missense NM_001407993.1:c.2219T>G NP_001394922.1:p.Leu740Arg missense NM_001408392.1:c.2216T>G NP_001395321.1:p.Leu739Arg missense NM_001408396.1:c.2216T>G NP_001395325.1:p.Leu739Arg missense NM_001408397.1:c.2216T>G NP_001395326.1:p.Leu739Arg missense NM_001408398.1:c.2216T>G NP_001395327.1:p.Leu739Arg missense NM_001408399.1:c.2216T>G NP_001395328.1:p.Leu739Arg missense NM_001408400.1:c.2216T>G NP_001395329.1:p.Leu739Arg missense NM_001408401.1:c.2216T>G NP_001395330.1:p.Leu739Arg missense NM_001408402.1:c.2216T>G NP_001395331.1:p.Leu739Arg missense NM_001408403.1:c.2216T>G NP_001395332.1:p.Leu739Arg missense NM_001408404.1:c.2216T>G NP_001395333.1:p.Leu739Arg missense NM_001408406.1:c.2213T>G NP_001395335.1:p.Leu738Arg missense NM_001408407.1:c.2213T>G NP_001395336.1:p.Leu738Arg missense NM_001408408.1:c.2213T>G NP_001395337.1:p.Leu738Arg missense NM_001408409.1:c.2210T>G NP_001395338.1:p.Leu737Arg missense NM_001408410.1:c.2147T>G NP_001395339.1:p.Leu716Arg missense NM_001408411.1:c.2144T>G NP_001395340.1:p.Leu715Arg missense NM_001408412.1:c.2141T>G NP_001395341.1:p.Leu714Arg missense NM_001408413.1:c.2141T>G NP_001395342.1:p.Leu714Arg missense NM_001408414.1:c.2141T>G NP_001395343.1:p.Leu714Arg missense NM_001408415.1:c.2141T>G NP_001395344.1:p.Leu714Arg missense NM_001408416.1:c.2141T>G NP_001395345.1:p.Leu714Arg missense NM_001408418.1:c.2105T>G NP_001395347.1:p.Leu702Arg missense NM_001408419.1:c.2105T>G NP_001395348.1:p.Leu702Arg missense NM_001408420.1:c.2105T>G NP_001395349.1:p.Leu702Arg missense NM_001408421.1:c.2102T>G NP_001395350.1:p.Leu701Arg missense NM_001408422.1:c.2102T>G NP_001395351.1:p.Leu701Arg missense NM_001408423.1:c.2102T>G NP_001395352.1:p.Leu701Arg missense NM_001408424.1:c.2102T>G NP_001395353.1:p.Leu701Arg missense NM_001408425.1:c.2099T>G NP_001395354.1:p.Leu700Arg missense NM_001408426.1:c.2099T>G NP_001395355.1:p.Leu700Arg missense NM_001408427.1:c.2099T>G NP_001395356.1:p.Leu700Arg missense NM_001408428.1:c.2099T>G NP_001395357.1:p.Leu700Arg missense NM_001408429.1:c.2099T>G NP_001395358.1:p.Leu700Arg missense NM_001408430.1:c.2099T>G NP_001395359.1:p.Leu700Arg missense NM_001408431.1:c.2099T>G NP_001395360.1:p.Leu700Arg missense NM_001408432.1:c.2096T>G NP_001395361.1:p.Leu699Arg missense NM_001408433.1:c.2096T>G NP_001395362.1:p.Leu699Arg missense NM_001408434.1:c.2096T>G NP_001395363.1:p.Leu699Arg missense NM_001408435.1:c.2096T>G NP_001395364.1:p.Leu699Arg missense NM_001408436.1:c.2096T>G NP_001395365.1:p.Leu699Arg missense NM_001408437.1:c.2096T>G NP_001395366.1:p.Leu699Arg missense NM_001408438.1:c.2096T>G NP_001395367.1:p.Leu699Arg missense NM_001408439.1:c.2096T>G NP_001395368.1:p.Leu699Arg missense NM_001408440.1:c.2096T>G NP_001395369.1:p.Leu699Arg missense NM_001408441.1:c.2096T>G NP_001395370.1:p.Leu699Arg missense NM_001408442.1:c.2096T>G NP_001395371.1:p.Leu699Arg missense NM_001408443.1:c.2096T>G NP_001395372.1:p.Leu699Arg missense NM_001408444.1:c.2096T>G NP_001395373.1:p.Leu699Arg missense NM_001408445.1:c.2093T>G NP_001395374.1:p.Leu698Arg missense NM_001408446.1:c.2093T>G NP_001395375.1:p.Leu698Arg missense NM_001408447.1:c.2093T>G NP_001395376.1:p.Leu698Arg missense NM_001408448.1:c.2093T>G NP_001395377.1:p.Leu698Arg missense NM_001408450.1:c.2093T>G NP_001395379.1:p.Leu698Arg missense NM_001408451.1:c.2087T>G NP_001395380.1:p.Leu696Arg missense NM_001408452.1:c.2081T>G NP_001395381.1:p.Leu694Arg missense NM_001408453.1:c.2081T>G NP_001395382.1:p.Leu694Arg missense NM_001408454.1:c.2081T>G NP_001395383.1:p.Leu694Arg missense NM_001408455.1:c.2081T>G NP_001395384.1:p.Leu694Arg missense NM_001408456.1:c.2081T>G NP_001395385.1:p.Leu694Arg missense NM_001408457.1:c.2081T>G NP_001395386.1:p.Leu694Arg missense NM_001408458.1:c.2078T>G NP_001395387.1:p.Leu693Arg missense NM_001408459.1:c.2078T>G NP_001395388.1:p.Leu693Arg missense NM_001408460.1:c.2078T>G NP_001395389.1:p.Leu693Arg missense NM_001408461.1:c.2078T>G NP_001395390.1:p.Leu693Arg missense NM_001408462.1:c.2078T>G NP_001395391.1:p.Leu693Arg missense NM_001408463.1:c.2078T>G NP_001395392.1:p.Leu693Arg missense NM_001408464.1:c.2078T>G NP_001395393.1:p.Leu693Arg missense NM_001408465.1:c.2078T>G NP_001395394.1:p.Leu693Arg missense NM_001408466.1:c.2078T>G NP_001395395.1:p.Leu693Arg missense NM_001408467.1:c.2078T>G NP_001395396.1:p.Leu693Arg missense NM_001408468.1:c.2075T>G NP_001395397.1:p.Leu692Arg missense NM_001408469.1:c.2075T>G NP_001395398.1:p.Leu692Arg missense NM_001408470.1:c.2075T>G NP_001395399.1:p.Leu692Arg missense NM_001408472.1:c.*45T>G NM_001408473.1:c.*45T>G NM_001408474.1:c.2021T>G NP_001395403.1:p.Leu674Arg missense NM_001408475.1:c.2018T>G NP_001395404.1:p.Leu673Arg missense NM_001408476.1:c.2018T>G NP_001395405.1:p.Leu673Arg missense NM_001408478.1:c.2012T>G NP_001395407.1:p.Leu671Arg missense NM_001408479.1:c.2012T>G NP_001395408.1:p.Leu671Arg missense NM_001408480.1:c.2012T>G NP_001395409.1:p.Leu671Arg missense NM_001408481.1:c.2009T>G NP_001395410.1:p.Leu670Arg missense NM_001408482.1:c.2009T>G NP_001395411.1:p.Leu670Arg missense NM_001408483.1:c.2009T>G NP_001395412.1:p.Leu670Arg missense NM_001408484.1:c.2009T>G NP_001395413.1:p.Leu670Arg missense NM_001408485.1:c.2009T>G NP_001395414.1:p.Leu670Arg missense NM_001408489.1:c.2009T>G NP_001395418.1:p.Leu670Arg missense NM_001408490.1:c.2009T>G NP_001395419.1:p.Leu670Arg missense NM_001408491.1:c.2009T>G NP_001395420.1:p.Leu670Arg missense NM_001408492.1:c.2006T>G NP_001395421.1:p.Leu669Arg missense NM_001408493.1:c.2006T>G NP_001395422.1:p.Leu669Arg missense NM_001408494.1:c.1982T>G NP_001395423.1:p.Leu661Arg missense NM_001408495.1:c.1976T>G NP_001395424.1:p.Leu659Arg missense NM_001408496.1:c.1958T>G NP_001395425.1:p.Leu653Arg missense NM_001408497.1:c.1958T>G NP_001395426.1:p.Leu653Arg missense NM_001408498.1:c.1958T>G NP_001395427.1:p.Leu653Arg missense NM_001408499.1:c.1958T>G NP_001395428.1:p.Leu653Arg missense NM_001408500.1:c.1958T>G NP_001395429.1:p.Leu653Arg missense NM_001408501.1:c.1958T>G NP_001395430.1:p.Leu653Arg missense NM_001408502.1:c.1955T>G NP_001395431.1:p.Leu652Arg missense NM_001408503.1:c.1955T>G NP_001395432.1:p.Leu652Arg missense NM_001408504.1:c.1955T>G NP_001395433.1:p.Leu652Arg missense NM_001408505.1:c.1952T>G NP_001395434.1:p.Leu651Arg missense NM_001408506.1:c.1895T>G NP_001395435.1:p.Leu632Arg missense NM_001408507.1:c.1892T>G NP_001395436.1:p.Leu631Arg missense NM_001408508.1:c.1883T>G NP_001395437.1:p.Leu628Arg missense NM_001408509.1:c.1880T>G NP_001395438.1:p.Leu627Arg missense NM_001408510.1:c.1841T>G NP_001395439.1:p.Leu614Arg missense NM_001408511.1:c.1838T>G NP_001395440.1:p.Leu613Arg missense NM_001408512.1:c.1718T>G NP_001395441.1:p.Leu573Arg missense NM_001408513.1:c.1691T>G NP_001395442.1:p.Leu564Arg missense NM_001408514.1:c.1295T>G NP_001395443.1:p.Leu432Arg missense NM_007297.4:c.5390T>G NP_009228.2:p.Leu1797Arg missense NM_007298.4:c.2219T>G NP_009229.2:p.Leu740Arg missense NM_007299.4:c.*45T>G 3 prime UTR NM_007300.4:c.5594T>G NP_009231.2:p.Leu1865Arg missense NM_007304.2:c.2219T>G NP_009235.2:p.Leu740Arg missense NR_027676.2:n.5708T>G non-coding transcript variant NC_000017.11:g.43045739A>C NC_000017.10:g.41197756A>C NG_005905.2:g.172245T>G LRG_292:g.172245T>G LRG_292t1:c.5531T>G LRG_292p1:p.Leu1844Arg U14680.1:n.5650T>G - Protein change
- L1844R, L740R, L1865R, L1797R, L1732R, L1775R, L1776R, L1796R, L1801R, L1825R, L1841R, L1864R, L573R, L627R, L628R, L631R, L653R, L659R, L739R, L1675R, L1690R, L1754R, L1756R, L1760R, L1800R, L1803R, L1817R, L1842R, L1866R, L564R, L613R, L632R, L651R, L692R, L698R, L699R, L702R, L716R, L975R, L976R, L1548R, L1717R, L1731R, L1755R, L1772R, L1773R, L1802R, L1818R, L1824R, L1840R, L614R, L652R, L671R, L674R, L696R, L701R, L738R, L741R, L1547R, L1715R, L1716R, L1733R, L1774R, L1777R, L1795R, L1816R, L1839R, L1843R, L432R, L661R, L669R, L670R, L673R, L693R, L694R, L700R, L714R, L715R, L737R, L762R, L763R
- Other names
-
p.L1844R:CTC>CGC
5650T>G
- Canonical SPDI
- NC_000017.11:43045738:A:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
functionally_normal; Sequence Ontology [ SO:0002219]The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5531T>G, a MISSENSE variant, produced a function score of -0.06, corresponding to a functional classification of FUNCTIONAL. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. [submitted by Brotman Baty Institute, University of Washington]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13044 | 14850 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Benign (5) |
reviewed by expert panel
|
Jun 18, 2019 | RCV000083221.19 | |
| Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 26, 2022 | RCV000131565.22 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 17, 2018 | RCV000586607.19 | |
| Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 28, 2024 | RCV000709463.19 | |
| Likely benign (1) |
criteria provided, single submitter
|
Mar 19, 2024 | RCV000855577.13 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001358221.10 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Jun 18, 2019)
|
reviewed by expert panel
Method: curation
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV001161503.2
First in ClinVar: Feb 16, 2020 Last updated: Jan 07, 2023 |
Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on … (more)
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000321 (less)
|
|
|
Uncertain significance
(Jun 09, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000228064.5
First in ClinVar: Jun 29, 2015 Last updated: Mar 17, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Likely benign
(Jul 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000683333.5
First in ClinVar: Feb 19, 2018 Last updated: Jan 08, 2022 |
|
|
|
Likely benign
(Jan 26, 2022)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537870.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Uncertain significance
(Nov 02, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489614.2
First in ClinVar: Sep 27, 2014 Last updated: Dec 24, 2022 |
|
|
|
Benign
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV000839207.3
First in ClinVar: Oct 10, 2018 Last updated: Aug 25, 2023 |
|
|
|
Likely benign
(Oct 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186569.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Jul 24, 2018)
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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: SCV000209994.13
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
This variant is denoted BRCA1 c.5531T>G at the cDNA level, p.Leu1844Arg (L1844R) at the protein level, and results in the change of a Leucine to … (more)
This variant is denoted BRCA1 c.5531T>G at the cDNA level, p.Leu1844Arg (L1844R) at the protein level, and results in the change of a Leucine to an Arginine (CTC>CGC). This variant, also known as BRCA1 5650T>G using alternate nomenclature, was reported as having an uncertain clinical effect based on biochemical and cell-based transcriptional assays (Lee 2010). This variant has been observed in at least one HBOC family and at least one individual with breast cancer (Peixoto 2014, Dean 2015). BRCA1 Leu1844Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain and a region known to interact with multiple proteins (UniProt, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Leu1844Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Sep 17, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001133641.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 03, 2022 |
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Likely benign
(Jan 28, 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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001615582.4
First in ClinVar: May 16, 2021 Last updated: Feb 28, 2024 |
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Likely benign
(Mar 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699270.6
First in ClinVar: Mar 17, 2018 Last updated: Jun 29, 2024 |
Comment:
Variant summary: BRCA1 c.5531T>G (p.Leu1844Arg) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of … (more)
Variant summary: BRCA1 c.5531T>G (p.Leu1844Arg) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250824 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5531T>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Dean_2015, Peixoto_2014, Judkins_2005, Guindalini_2022, deOliveira_2022) and in an individual with Sebacious Carcinoma in whom a different somatic etiology, namely a somatic inactivation of MSH2 and MSH6 genes was reported (Wield_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several publications report experimental evidence evaluating an impact on protein function by transcriptional activation assays (example, Lee_2010, Woods_2016, Fernandes_2019). These results have consistently demonstrated no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 24845084, 26543556, 30765603, 35264596, 16267036, 17305420, 20516115, 24916970, 30225334, 28781887, 35534704, Iversen et al). ClinVar contains an entry for this variant (Variation ID: 55615). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(May 01, 2012)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000115295.3
First in ClinVar: Feb 06, 2014 Last updated: Sep 27, 2014 |
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Uncertain significance
(Nov 02, 2017)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000778731.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
|
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553895.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRCA1 p.Leu1844Arg variant was identified in 2 of 2340 proband chromosomes (frequency: 0.0009) from individuals or families with breast and ovarian cancer (Dean 2015, … (more)
The BRCA1 p.Leu1844Arg variant was identified in 2 of 2340 proband chromosomes (frequency: 0.0009) from individuals or families with breast and ovarian cancer (Dean 2015, Peixoto 2015). The variant identified in dbSNP (rs80357323) as “with uncertain significance allele”, ClinVar (interpreted as "uncertain significance by Ambry Genetics and 7 others and “likely benign" by SCRP), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 5 of 245,562 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 15,300 chromosomes (freq: 0.0001), Ashkenazi Jewish in 3 of 9820 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Latino, European, East Asian, Finnish, and South Asian populations. The functional effect of the p.Leu1844Arg missense variant was assessed in a series of assays. Based on the nonconcordant results in binding, protease sensitivity and structural stability assays, the variant was classified as having an uncertain functional effect (Lee 2010). The p.Leu1844 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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not provided
(-)
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no classification provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145568.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian Non Hispanic
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Jewish
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not provided
(-)
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no classification provided
Method: in vitro
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Breast-ovarian cancer, familial 1
Affected status: not applicable
Allele origin:
not applicable
|
Brotman Baty Institute, University of Washington
Accession: SCV001243514.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
FUNCTIONAL:-0.0615812686944012
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| click to load more click to collapse | |||||
Comment:
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
This variant is denoted BRCA1 c.5531T>G at the cDNA level, p.Leu1844Arg (L1844R) at the protein level, and results in the change of a Leucine to an Arginine (CTC>CGC). This variant, also known as BRCA1 5650T>G using alternate nomenclature, was reported as having an uncertain clinical effect based on biochemical and cell-based transcriptional assays (Lee 2010). This variant has been observed in at least one HBOC family and at least one individual with breast cancer (Peixoto 2014, Dean 2015). BRCA1 Leu1844Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain and a region known to interact with multiple proteins (UniProt, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Leu1844Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Comment:
Variant summary: BRCA1 c.5531T>G (p.Leu1844Arg) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250824 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5531T>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Dean_2015, Peixoto_2014, Judkins_2005, Guindalini_2022, deOliveira_2022) and in an individual with Sebacious Carcinoma in whom a different somatic etiology, namely a somatic inactivation of MSH2 and MSH6 genes was reported (Wield_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several publications report experimental evidence evaluating an impact on protein function by transcriptional activation assays (example, Lee_2010, Woods_2016, Fernandes_2019). These results have consistently demonstrated no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 24845084, 26543556, 30765603, 35264596, 16267036, 17305420, 20516115, 24916970, 30225334, 28781887, 35534704, Iversen et al). ClinVar contains an entry for this variant (Variation ID: 55615). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
The BRCA1 p.Leu1844Arg variant was identified in 2 of 2340 proband chromosomes (frequency: 0.0009) from individuals or families with breast and ovarian cancer (Dean 2015, Peixoto 2015). The variant identified in dbSNP (rs80357323) as “with uncertain significance allele”, ClinVar (interpreted as "uncertain significance by Ambry Genetics and 7 others and “likely benign" by SCRP), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 5 of 245,562 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 15,300 chromosomes (freq: 0.0001), Ashkenazi Jewish in 3 of 9820 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Latino, European, East Asian, Finnish, and South Asian populations. The functional effect of the p.Leu1844Arg missense variant was assessed in a series of assays. Based on the nonconcordant results in binding, protease sensitivity and structural stability assays, the variant was classified as having an uncertain functional effect (Lee 2010). The p.Leu1844 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
functionally_normal
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Method citation(s):
|
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Brotman Baty Institute, University of Washington
Accession: SCV001243514.1
|
Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5531T>G, a MISSENSE variant, produced a function score of -0.06, corresponding to a functional classification of FUNCTIONAL. … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5531T>G, a MISSENSE variant, produced a function score of -0.06, corresponding to a functional classification of FUNCTIONAL. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. (less)
|
Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000321
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
This variant is denoted BRCA1 c.5531T>G at the cDNA level, p.Leu1844Arg (L1844R) at the protein level, and results in the change of a Leucine to an Arginine (CTC>CGC). This variant, also known as BRCA1 5650T>G using alternate nomenclature, was reported as having an uncertain clinical effect based on biochemical and cell-based transcriptional assays (Lee 2010). This variant has been observed in at least one HBOC family and at least one individual with breast cancer (Peixoto 2014, Dean 2015). BRCA1 Leu1844Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain and a region known to interact with multiple proteins (UniProt, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Leu1844Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Comment:
Variant summary: BRCA1 c.5531T>G (p.Leu1844Arg) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250824 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5531T>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Dean_2015, Peixoto_2014, Judkins_2005, Guindalini_2022, deOliveira_2022) and in an individual with Sebacious Carcinoma in whom a different somatic etiology, namely a somatic inactivation of MSH2 and MSH6 genes was reported (Wield_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several publications report experimental evidence evaluating an impact on protein function by transcriptional activation assays (example, Lee_2010, Woods_2016, Fernandes_2019). These results have consistently demonstrated no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 24845084, 26543556, 30765603, 35264596, 16267036, 17305420, 20516115, 24916970, 30225334, 28781887, 35534704, Iversen et al). ClinVar contains an entry for this variant (Variation ID: 55615). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
The BRCA1 p.Leu1844Arg variant was identified in 2 of 2340 proband chromosomes (frequency: 0.0009) from individuals or families with breast and ovarian cancer (Dean 2015, Peixoto 2015). The variant identified in dbSNP (rs80357323) as “with uncertain significance allele”, ClinVar (interpreted as "uncertain significance by Ambry Genetics and 7 others and “likely benign" by SCRP), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 5 of 245,562 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 15,300 chromosomes (freq: 0.0001), Ashkenazi Jewish in 3 of 9820 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Latino, European, East Asian, Finnish, and South Asian populations. The functional effect of the p.Leu1844Arg missense variant was assessed in a series of assays. Based on the nonconcordant results in binding, protease sensitivity and structural stability assays, the variant was classified as having an uncertain functional effect (Lee 2010). The p.Leu1844 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients. | de Oliveira JM | European journal of human genetics : EJHG | 2022 | PMID: 35534704 |
| Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. | Guindalini RSC | Scientific reports | 2022 | PMID: 35264596 |
| 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 |
| Sebaceous carcinoma arising within an ovarian mature cystic teratoma: A case report with discussion of clinical management and genetic evaluation. | Wield A | Gynecologic oncology reports | 2018 | PMID: 30225334 |
| Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
| Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. | Woods NT | NPJ genomic medicine | 2016 | PMID: 28781887 |
| Addressing health disparities in Hispanic breast cancer: accurate and inexpensive sequencing of BRCA1 and BRCA2. | Dean M | GigaScience | 2015 | PMID: 26543556 |
| The role of targeted BRCA1/BRCA2 mutation analysis in hereditary breast/ovarian cancer families of Portuguese ancestry. | Peixoto A | Clinical genetics | 2015 | PMID: 24916970 |
| Probing structure-function relationships in missense variants in the carboxy-terminal region of BRCA1. | Carvalho RS | PloS one | 2014 | PMID: 24845084 |
| A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1. | Iversen ES Jr | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2011 | PMID: 21447777 |
| Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. | Lee MS | Cancer research | 2010 | PMID: 20516115 |
| Functional impact of missense variants in BRCA1 predicted by supervised learning. | Karchin R | PLoS computational biology | 2007 | PMID: 17305420 |
| Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. | Judkins T | Cancer research | 2005 | PMID: 16267036 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA1 | - | - | - | - |
| https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
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Text-mined citations for rs80357323 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.