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.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.4213A>G (p.Ile1405Val)
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.
(11)
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(1); Likely benign(7)
Uncertain significance(1); Likely benign(7)
11
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.4213A>G (p.Ile1405Val)
Variation ID: 37575 Accession: VCV000037575.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.31 17: 43082548 (GRCh38) [ NCBI UCSC ] 17: 41234565 (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 May 1, 2024 Oct 3, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.4213A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Ile1405Val missense NM_001407571.1:c.4000A>G NP_001394500.1:p.Ile1334Val missense NM_001407581.1:c.4213A>G NP_001394510.1:p.Ile1405Val missense NM_001407582.1:c.4213A>G NP_001394511.1:p.Ile1405Val missense NM_001407583.1:c.4213A>G NP_001394512.1:p.Ile1405Val missense NM_001407585.1:c.4213A>G NP_001394514.1:p.Ile1405Val missense NM_001407587.1:c.4210A>G NP_001394516.1:p.Ile1404Val missense NM_001407590.1:c.4210A>G NP_001394519.1:p.Ile1404Val missense NM_001407591.1:c.4210A>G NP_001394520.1:p.Ile1404Val missense NM_001407593.1:c.4213A>G NP_001394522.1:p.Ile1405Val missense NM_001407594.1:c.4213A>G NP_001394523.1:p.Ile1405Val missense NM_001407596.1:c.4213A>G NP_001394525.1:p.Ile1405Val missense NM_001407597.1:c.4213A>G NP_001394526.1:p.Ile1405Val missense NM_001407598.1:c.4213A>G NP_001394527.1:p.Ile1405Val missense NM_001407602.1:c.4213A>G NP_001394531.1:p.Ile1405Val missense NM_001407603.1:c.4213A>G NP_001394532.1:p.Ile1405Val missense NM_001407605.1:c.4213A>G NP_001394534.1:p.Ile1405Val missense NM_001407610.1:c.4210A>G NP_001394539.1:p.Ile1404Val missense NM_001407611.1:c.4210A>G NP_001394540.1:p.Ile1404Val missense NM_001407612.1:c.4210A>G NP_001394541.1:p.Ile1404Val missense NM_001407613.1:c.4210A>G NP_001394542.1:p.Ile1404Val missense NM_001407614.1:c.4210A>G NP_001394543.1:p.Ile1404Val missense NM_001407615.1:c.4210A>G NP_001394544.1:p.Ile1404Val missense NM_001407616.1:c.4213A>G NP_001394545.1:p.Ile1405Val missense NM_001407617.1:c.4213A>G NP_001394546.1:p.Ile1405Val missense NM_001407618.1:c.4213A>G NP_001394547.1:p.Ile1405Val missense NM_001407619.1:c.4213A>G NP_001394548.1:p.Ile1405Val missense NM_001407620.1:c.4213A>G NP_001394549.1:p.Ile1405Val missense NM_001407621.1:c.4213A>G NP_001394550.1:p.Ile1405Val missense NM_001407622.1:c.4213A>G NP_001394551.1:p.Ile1405Val missense NM_001407623.1:c.4213A>G NP_001394552.1:p.Ile1405Val missense NM_001407624.1:c.4210A>G NP_001394553.1:p.Ile1404Val missense NM_001407625.1:c.4210A>G NP_001394554.1:p.Ile1404Val missense NM_001407626.1:c.4210A>G NP_001394555.1:p.Ile1404Val missense NM_001407627.1:c.4207A>G NP_001394556.1:p.Ile1403Val missense NM_001407628.1:c.4207A>G NP_001394557.1:p.Ile1403Val missense NM_001407629.1:c.4207A>G NP_001394558.1:p.Ile1403Val missense NM_001407630.1:c.4207A>G NP_001394559.1:p.Ile1403Val missense NM_001407631.1:c.4207A>G NP_001394560.1:p.Ile1403Val missense NM_001407632.1:c.4207A>G NP_001394561.1:p.Ile1403Val missense NM_001407633.1:c.4210A>G NP_001394562.1:p.Ile1404Val missense NM_001407634.1:c.4210A>G NP_001394563.1:p.Ile1404Val missense NM_001407635.1:c.4210A>G NP_001394564.1:p.Ile1404Val missense NM_001407636.1:c.4210A>G NP_001394565.1:p.Ile1404Val missense NM_001407637.1:c.4210A>G NP_001394566.1:p.Ile1404Val missense NM_001407638.1:c.4210A>G NP_001394567.1:p.Ile1404Val missense NM_001407639.1:c.4210A>G NP_001394568.1:p.Ile1404Val missense NM_001407640.1:c.4210A>G NP_001394569.1:p.Ile1404Val missense NM_001407641.1:c.4210A>G NP_001394570.1:p.Ile1404Val missense NM_001407642.1:c.4210A>G NP_001394571.1:p.Ile1404Val missense NM_001407644.1:c.4207A>G NP_001394573.1:p.Ile1403Val missense NM_001407645.1:c.4207A>G NP_001394574.1:p.Ile1403Val missense NM_001407646.1:c.4201A>G NP_001394575.1:p.Ile1401Val missense NM_001407647.1:c.4201A>G NP_001394576.1:p.Ile1401Val missense NM_001407648.1:c.4090A>G NP_001394577.1:p.Ile1364Val missense NM_001407649.1:c.4087A>G NP_001394578.1:p.Ile1363Val missense NM_001407652.1:c.4213A>G NP_001394581.1:p.Ile1405Val missense NM_001407653.1:c.4135A>G NP_001394582.1:p.Ile1379Val missense NM_001407654.1:c.4135A>G NP_001394583.1:p.Ile1379Val missense NM_001407655.1:c.4135A>G NP_001394584.1:p.Ile1379Val missense NM_001407656.1:c.4132A>G NP_001394585.1:p.Ile1378Val missense NM_001407657.1:c.4135A>G NP_001394586.1:p.Ile1379Val missense NM_001407658.1:c.4135A>G NP_001394587.1:p.Ile1379Val missense NM_001407659.1:c.4129A>G NP_001394588.1:p.Ile1377Val missense NM_001407660.1:c.4129A>G NP_001394589.1:p.Ile1377Val missense NM_001407661.1:c.4132A>G NP_001394590.1:p.Ile1378Val missense NM_001407662.1:c.4132A>G NP_001394591.1:p.Ile1378Val missense NM_001407663.1:c.4132A>G NP_001394592.1:p.Ile1378Val missense NM_001407664.1:c.4090A>G NP_001394593.1:p.Ile1364Val missense NM_001407665.1:c.4090A>G NP_001394594.1:p.Ile1364Val missense NM_001407666.1:c.4090A>G NP_001394595.1:p.Ile1364Val missense NM_001407667.1:c.4090A>G NP_001394596.1:p.Ile1364Val missense NM_001407668.1:c.4090A>G NP_001394597.1:p.Ile1364Val missense NM_001407669.1:c.4090A>G NP_001394598.1:p.Ile1364Val missense NM_001407670.1:c.4087A>G NP_001394599.1:p.Ile1363Val missense NM_001407671.1:c.4087A>G NP_001394600.1:p.Ile1363Val missense NM_001407672.1:c.4087A>G NP_001394601.1:p.Ile1363Val missense NM_001407673.1:c.4087A>G NP_001394602.1:p.Ile1363Val missense NM_001407674.1:c.4087A>G NP_001394603.1:p.Ile1363Val missense NM_001407675.1:c.4087A>G NP_001394604.1:p.Ile1363Val missense NM_001407676.1:c.4087A>G NP_001394605.1:p.Ile1363Val missense NM_001407677.1:c.4090A>G NP_001394606.1:p.Ile1364Val missense NM_001407678.1:c.4090A>G NP_001394607.1:p.Ile1364Val missense NM_001407679.1:c.4090A>G NP_001394608.1:p.Ile1364Val missense NM_001407680.1:c.4090A>G NP_001394609.1:p.Ile1364Val missense NM_001407681.1:c.4087A>G NP_001394610.1:p.Ile1363Val missense NM_001407682.1:c.4087A>G NP_001394611.1:p.Ile1363Val missense NM_001407683.1:c.4087A>G NP_001394612.1:p.Ile1363Val missense NM_001407684.1:c.4213A>G NP_001394613.1:p.Ile1405Val missense NM_001407685.1:c.4084A>G NP_001394614.1:p.Ile1362Val missense NM_001407686.1:c.4084A>G NP_001394615.1:p.Ile1362Val missense NM_001407687.1:c.4084A>G NP_001394616.1:p.Ile1362Val missense NM_001407688.1:c.4087A>G NP_001394617.1:p.Ile1363Val missense NM_001407689.1:c.4087A>G NP_001394618.1:p.Ile1363Val missense NM_001407690.1:c.4084A>G NP_001394619.1:p.Ile1362Val missense NM_001407691.1:c.4084A>G NP_001394620.1:p.Ile1362Val missense NM_001407692.1:c.4072A>G NP_001394621.1:p.Ile1358Val missense NM_001407694.1:c.4072A>G NP_001394623.1:p.Ile1358Val missense NM_001407695.1:c.4072A>G NP_001394624.1:p.Ile1358Val missense NM_001407696.1:c.4072A>G NP_001394625.1:p.Ile1358Val missense NM_001407697.1:c.4072A>G NP_001394626.1:p.Ile1358Val missense NM_001407698.1:c.4072A>G NP_001394627.1:p.Ile1358Val missense NM_001407724.1:c.4072A>G NP_001394653.1:p.Ile1358Val missense NM_001407725.1:c.4072A>G NP_001394654.1:p.Ile1358Val missense NM_001407726.1:c.4072A>G NP_001394655.1:p.Ile1358Val missense NM_001407727.1:c.4072A>G NP_001394656.1:p.Ile1358Val missense NM_001407728.1:c.4072A>G NP_001394657.1:p.Ile1358Val missense NM_001407729.1:c.4072A>G NP_001394658.1:p.Ile1358Val missense NM_001407730.1:c.4072A>G NP_001394659.1:p.Ile1358Val missense NM_001407731.1:c.4072A>G NP_001394660.1:p.Ile1358Val missense NM_001407732.1:c.4072A>G NP_001394661.1:p.Ile1358Val missense NM_001407733.1:c.4072A>G NP_001394662.1:p.Ile1358Val missense NM_001407734.1:c.4072A>G NP_001394663.1:p.Ile1358Val missense NM_001407735.1:c.4072A>G NP_001394664.1:p.Ile1358Val missense NM_001407736.1:c.4072A>G NP_001394665.1:p.Ile1358Val missense NM_001407737.1:c.4072A>G NP_001394666.1:p.Ile1358Val missense NM_001407738.1:c.4072A>G NP_001394667.1:p.Ile1358Val missense NM_001407739.1:c.4072A>G NP_001394668.1:p.Ile1358Val missense NM_001407740.1:c.4069A>G NP_001394669.1:p.Ile1357Val missense NM_001407741.1:c.4069A>G NP_001394670.1:p.Ile1357Val missense NM_001407742.1:c.4069A>G NP_001394671.1:p.Ile1357Val missense NM_001407743.1:c.4069A>G NP_001394672.1:p.Ile1357Val missense NM_001407744.1:c.4069A>G NP_001394673.1:p.Ile1357Val missense NM_001407745.1:c.4069A>G NP_001394674.1:p.Ile1357Val missense NM_001407746.1:c.4069A>G NP_001394675.1:p.Ile1357Val missense NM_001407747.1:c.4069A>G NP_001394676.1:p.Ile1357Val missense NM_001407748.1:c.4069A>G NP_001394677.1:p.Ile1357Val missense NM_001407749.1:c.4069A>G NP_001394678.1:p.Ile1357Val missense NM_001407750.1:c.4069A>G NP_001394679.1:p.Ile1357Val missense NM_001407751.1:c.4069A>G NP_001394680.1:p.Ile1357Val missense NM_001407752.1:c.4069A>G NP_001394681.1:p.Ile1357Val missense NM_001407838.1:c.4069A>G NP_001394767.1:p.Ile1357Val missense NM_001407839.1:c.4069A>G NP_001394768.1:p.Ile1357Val missense NM_001407841.1:c.4069A>G NP_001394770.1:p.Ile1357Val missense NM_001407842.1:c.4069A>G NP_001394771.1:p.Ile1357Val missense NM_001407843.1:c.4069A>G NP_001394772.1:p.Ile1357Val missense NM_001407844.1:c.4069A>G NP_001394773.1:p.Ile1357Val missense NM_001407845.1:c.4069A>G NP_001394774.1:p.Ile1357Val missense NM_001407846.1:c.4069A>G NP_001394775.1:p.Ile1357Val missense NM_001407847.1:c.4066A>G NP_001394776.1:p.Ile1356Val missense NM_001407848.1:c.4066A>G NP_001394777.1:p.Ile1356Val missense NM_001407849.1:c.4066A>G NP_001394778.1:p.Ile1356Val missense NM_001407850.1:c.4069A>G NP_001394779.1:p.Ile1357Val missense NM_001407851.1:c.4069A>G NP_001394780.1:p.Ile1357Val missense NM_001407852.1:c.4069A>G NP_001394781.1:p.Ile1357Val missense NM_001407853.1:c.4000A>G NP_001394782.1:p.Ile1334Val missense NM_001407854.1:c.4213A>G NP_001394783.1:p.Ile1405Val missense NM_001407858.1:c.4213A>G NP_001394787.1:p.Ile1405Val missense NM_001407859.1:c.4213A>G NP_001394788.1:p.Ile1405Val missense NM_001407860.1:c.4210A>G NP_001394789.1:p.Ile1404Val missense NM_001407861.1:c.4210A>G NP_001394790.1:p.Ile1404Val missense NM_001407862.1:c.4012A>G NP_001394791.1:p.Ile1338Val missense NM_001407863.1:c.4090A>G NP_001394792.1:p.Ile1364Val missense NM_001407874.1:c.4009A>G NP_001394803.1:p.Ile1337Val missense NM_001407875.1:c.4009A>G NP_001394804.1:p.Ile1337Val missense NM_001407879.1:c.4003A>G NP_001394808.1:p.Ile1335Val missense NM_001407881.1:c.4003A>G NP_001394810.1:p.Ile1335Val missense NM_001407882.1:c.4003A>G NP_001394811.1:p.Ile1335Val missense NM_001407884.1:c.4003A>G NP_001394813.1:p.Ile1335Val missense NM_001407885.1:c.4003A>G NP_001394814.1:p.Ile1335Val missense NM_001407886.1:c.4003A>G NP_001394815.1:p.Ile1335Val missense NM_001407887.1:c.4003A>G NP_001394816.1:p.Ile1335Val missense NM_001407889.1:c.4003A>G NP_001394818.1:p.Ile1335Val missense NM_001407894.1:c.4000A>G NP_001394823.1:p.Ile1334Val missense NM_001407895.1:c.4000A>G NP_001394824.1:p.Ile1334Val missense NM_001407896.1:c.4000A>G NP_001394825.1:p.Ile1334Val missense NM_001407897.1:c.4000A>G NP_001394826.1:p.Ile1334Val missense NM_001407898.1:c.4000A>G NP_001394827.1:p.Ile1334Val missense NM_001407899.1:c.4000A>G NP_001394828.1:p.Ile1334Val missense NM_001407900.1:c.4003A>G NP_001394829.1:p.Ile1335Val missense NM_001407902.1:c.4003A>G NP_001394831.1:p.Ile1335Val missense NM_001407904.1:c.4003A>G NP_001394833.1:p.Ile1335Val missense NM_001407906.1:c.4003A>G NP_001394835.1:p.Ile1335Val missense NM_001407907.1:c.4000A>G NP_001394836.1:p.Ile1334Val missense NM_001407908.1:c.4000A>G NP_001394837.1:p.Ile1334Val missense NM_001407909.1:c.4000A>G NP_001394838.1:p.Ile1334Val missense NM_001407910.1:c.4000A>G NP_001394839.1:p.Ile1334Val missense NM_001407915.1:c.3997A>G NP_001394844.1:p.Ile1333Val missense NM_001407916.1:c.4000A>G NP_001394845.1:p.Ile1334Val missense NM_001407917.1:c.4000A>G NP_001394846.1:p.Ile1334Val missense NM_001407918.1:c.4000A>G NP_001394847.1:p.Ile1334Val missense NM_001407919.1:c.4090A>G NP_001394848.1:p.Ile1364Val missense NM_001407920.1:c.3949A>G NP_001394849.1:p.Ile1317Val missense NM_001407921.1:c.3949A>G NP_001394850.1:p.Ile1317Val missense NM_001407922.1:c.3949A>G NP_001394851.1:p.Ile1317Val missense NM_001407923.1:c.3949A>G NP_001394852.1:p.Ile1317Val missense NM_001407924.1:c.3949A>G NP_001394853.1:p.Ile1317Val missense NM_001407925.1:c.3949A>G NP_001394854.1:p.Ile1317Val missense NM_001407926.1:c.3949A>G NP_001394855.1:p.Ile1317Val missense NM_001407927.1:c.3949A>G NP_001394856.1:p.Ile1317Val missense NM_001407928.1:c.3949A>G NP_001394857.1:p.Ile1317Val missense NM_001407929.1:c.3949A>G NP_001394858.1:p.Ile1317Val missense NM_001407930.1:c.3946A>G NP_001394859.1:p.Ile1316Val missense NM_001407931.1:c.3946A>G NP_001394860.1:p.Ile1316Val missense NM_001407932.1:c.3946A>G NP_001394861.1:p.Ile1316Val missense NM_001407933.1:c.3946A>G NP_001394862.1:p.Ile1316Val missense NM_001407934.1:c.3943A>G NP_001394863.1:p.Ile1315Val missense NM_001407935.1:c.3946A>G NP_001394864.1:p.Ile1316Val missense NM_001407936.1:c.3946A>G NP_001394865.1:p.Ile1316Val missense NM_001407937.1:c.4090A>G NP_001394866.1:p.Ile1364Val missense NM_001407938.1:c.4090A>G NP_001394867.1:p.Ile1364Val missense NM_001407939.1:c.4090A>G NP_001394868.1:p.Ile1364Val missense NM_001407940.1:c.4087A>G NP_001394869.1:p.Ile1363Val missense NM_001407941.1:c.4087A>G NP_001394870.1:p.Ile1363Val missense NM_001407942.1:c.4072A>G NP_001394871.1:p.Ile1358Val missense NM_001407943.1:c.4069A>G NP_001394872.1:p.Ile1357Val missense NM_001407944.1:c.4072A>G NP_001394873.1:p.Ile1358Val missense NM_001407945.1:c.4072A>G NP_001394874.1:p.Ile1358Val missense NM_001407946.1:c.3880A>G NP_001394875.1:p.Ile1294Val missense NM_001407947.1:c.3880A>G NP_001394876.1:p.Ile1294Val missense NM_001407948.1:c.3880A>G NP_001394877.1:p.Ile1294Val missense NM_001407949.1:c.3880A>G NP_001394878.1:p.Ile1294Val missense NM_001407950.1:c.3880A>G NP_001394879.1:p.Ile1294Val missense NM_001407951.1:c.3880A>G NP_001394880.1:p.Ile1294Val missense NM_001407952.1:c.3877A>G NP_001394881.1:p.Ile1293Val missense NM_001407953.1:c.3877A>G NP_001394882.1:p.Ile1293Val missense NM_001407954.1:c.3877A>G NP_001394883.1:p.Ile1293Val missense NM_001407955.1:c.3877A>G NP_001394884.1:p.Ile1293Val missense NM_001407956.1:c.3874A>G NP_001394885.1:p.Ile1292Val missense NM_001407957.1:c.3877A>G NP_001394886.1:p.Ile1293Val missense NM_001407958.1:c.3877A>G NP_001394887.1:p.Ile1293Val missense NM_001407959.1:c.3832A>G NP_001394888.1:p.Ile1278Val missense NM_001407960.1:c.3832A>G NP_001394889.1:p.Ile1278Val missense NM_001407962.1:c.3829A>G NP_001394891.1:p.Ile1277Val missense NM_001407963.1:c.3829A>G NP_001394892.1:p.Ile1277Val missense NM_001407964.1:c.4069A>G NP_001394893.1:p.Ile1357Val missense NM_001407965.1:c.3706A>G NP_001394894.1:p.Ile1236Val missense NM_001407966.1:c.3325A>G NP_001394895.1:p.Ile1109Val missense NM_001407967.1:c.3325A>G NP_001394896.1:p.Ile1109Val missense NM_001407968.1:c.1609A>G NP_001394897.1:p.Ile537Val missense NM_001407969.1:c.1606A>G NP_001394898.1:p.Ile536Val missense NM_001407970.1:c.904A>G NP_001394899.1:p.Ile302Val missense NM_001407971.1:c.904A>G NP_001394900.1:p.Ile302Val missense NM_001407972.1:c.901A>G NP_001394901.1:p.Ile301Val missense NM_001407973.1:c.904A>G NP_001394902.1:p.Ile302Val missense NM_001407974.1:c.904A>G NP_001394903.1:p.Ile302Val missense NM_001407975.1:c.904A>G NP_001394904.1:p.Ile302Val missense NM_001407976.1:c.904A>G NP_001394905.1:p.Ile302Val missense NM_001407977.1:c.904A>G NP_001394906.1:p.Ile302Val missense NM_001407978.1:c.904A>G NP_001394907.1:p.Ile302Val missense NM_001407979.1:c.901A>G NP_001394908.1:p.Ile301Val missense NM_001407980.1:c.901A>G NP_001394909.1:p.Ile301Val missense NM_001407981.1:c.901A>G NP_001394910.1:p.Ile301Val missense NM_001407982.1:c.901A>G NP_001394911.1:p.Ile301Val missense NM_001407983.1:c.901A>G NP_001394912.1:p.Ile301Val missense NM_001407984.1:c.901A>G NP_001394913.1:p.Ile301Val missense NM_001407985.1:c.901A>G NP_001394914.1:p.Ile301Val missense NM_001407986.1:c.901A>G NP_001394915.1:p.Ile301Val missense NM_001407990.1:c.901A>G NP_001394919.1:p.Ile301Val missense NM_001407991.1:c.901A>G NP_001394920.1:p.Ile301Val missense NM_001407992.1:c.901A>G NP_001394921.1:p.Ile301Val missense NM_001407993.1:c.904A>G NP_001394922.1:p.Ile302Val missense NM_001408392.1:c.901A>G NP_001395321.1:p.Ile301Val missense NM_001408396.1:c.901A>G NP_001395325.1:p.Ile301Val missense NM_001408397.1:c.901A>G NP_001395326.1:p.Ile301Val missense NM_001408398.1:c.901A>G NP_001395327.1:p.Ile301Val missense NM_001408399.1:c.901A>G NP_001395328.1:p.Ile301Val missense NM_001408400.1:c.898A>G NP_001395329.1:p.Ile300Val missense NM_001408401.1:c.898A>G NP_001395330.1:p.Ile300Val missense NM_001408402.1:c.898A>G NP_001395331.1:p.Ile300Val missense NM_001408403.1:c.901A>G NP_001395332.1:p.Ile301Val missense NM_001408404.1:c.901A>G NP_001395333.1:p.Ile301Val missense NM_001408406.1:c.895A>G NP_001395335.1:p.Ile299Val missense NM_001408407.1:c.898A>G NP_001395336.1:p.Ile300Val missense NM_001408408.1:c.895A>G NP_001395337.1:p.Ile299Val missense NM_001408409.1:c.826A>G NP_001395338.1:p.Ile276Val missense NM_001408410.1:c.763A>G NP_001395339.1:p.Ile255Val missense NM_001408411.1:c.826A>G NP_001395340.1:p.Ile276Val missense NM_001408412.1:c.826A>G NP_001395341.1:p.Ile276Val missense NM_001408413.1:c.823A>G NP_001395342.1:p.Ile275Val missense NM_001408414.1:c.826A>G NP_001395343.1:p.Ile276Val missense NM_001408415.1:c.826A>G NP_001395344.1:p.Ile276Val missense NM_001408416.1:c.823A>G NP_001395345.1:p.Ile275Val missense NM_001408418.1:c.787A>G NP_001395347.1:p.Ile263Val missense NM_001408419.1:c.787A>G NP_001395348.1:p.Ile263Val missense NM_001408420.1:c.787A>G NP_001395349.1:p.Ile263Val missense NM_001408421.1:c.784A>G NP_001395350.1:p.Ile262Val missense NM_001408422.1:c.787A>G NP_001395351.1:p.Ile263Val missense NM_001408423.1:c.787A>G NP_001395352.1:p.Ile263Val missense NM_001408424.1:c.784A>G NP_001395353.1:p.Ile262Val missense NM_001408425.1:c.781A>G NP_001395354.1:p.Ile261Val missense NM_001408426.1:c.781A>G NP_001395355.1:p.Ile261Val missense NM_001408427.1:c.781A>G NP_001395356.1:p.Ile261Val missense NM_001408428.1:c.781A>G NP_001395357.1:p.Ile261Val missense NM_001408429.1:c.781A>G NP_001395358.1:p.Ile261Val missense NM_001408430.1:c.781A>G NP_001395359.1:p.Ile261Val missense NM_001408431.1:c.784A>G NP_001395360.1:p.Ile262Val missense NM_001408432.1:c.778A>G NP_001395361.1:p.Ile260Val missense NM_001408433.1:c.778A>G NP_001395362.1:p.Ile260Val missense NM_001408434.1:c.778A>G NP_001395363.1:p.Ile260Val missense NM_001408435.1:c.778A>G NP_001395364.1:p.Ile260Val missense NM_001408436.1:c.781A>G NP_001395365.1:p.Ile261Val missense NM_001408437.1:c.781A>G NP_001395366.1:p.Ile261Val missense NM_001408438.1:c.781A>G NP_001395367.1:p.Ile261Val missense NM_001408439.1:c.781A>G NP_001395368.1:p.Ile261Val missense NM_001408440.1:c.781A>G NP_001395369.1:p.Ile261Val missense NM_001408441.1:c.778A>G NP_001395370.1:p.Ile260Val missense NM_001408442.1:c.778A>G NP_001395371.1:p.Ile260Val missense NM_001408443.1:c.778A>G NP_001395372.1:p.Ile260Val missense NM_001408444.1:c.778A>G NP_001395373.1:p.Ile260Val missense NM_001408445.1:c.778A>G NP_001395374.1:p.Ile260Val missense NM_001408446.1:c.778A>G NP_001395375.1:p.Ile260Val missense NM_001408447.1:c.778A>G NP_001395376.1:p.Ile260Val missense NM_001408448.1:c.778A>G NP_001395377.1:p.Ile260Val missense NM_001408450.1:c.778A>G NP_001395379.1:p.Ile260Val missense NM_001408451.1:c.769A>G NP_001395380.1:p.Ile257Val missense NM_001408452.1:c.763A>G NP_001395381.1:p.Ile255Val missense NM_001408453.1:c.763A>G NP_001395382.1:p.Ile255Val missense NM_001408454.1:c.763A>G NP_001395383.1:p.Ile255Val missense NM_001408455.1:c.763A>G NP_001395384.1:p.Ile255Val missense NM_001408456.1:c.763A>G NP_001395385.1:p.Ile255Val missense NM_001408457.1:c.763A>G NP_001395386.1:p.Ile255Val missense NM_001408458.1:c.763A>G NP_001395387.1:p.Ile255Val missense NM_001408459.1:c.763A>G NP_001395388.1:p.Ile255Val missense NM_001408460.1:c.763A>G NP_001395389.1:p.Ile255Val missense NM_001408461.1:c.763A>G NP_001395390.1:p.Ile255Val missense NM_001408462.1:c.760A>G NP_001395391.1:p.Ile254Val missense NM_001408463.1:c.760A>G NP_001395392.1:p.Ile254Val missense NM_001408464.1:c.760A>G NP_001395393.1:p.Ile254Val missense NM_001408465.1:c.760A>G NP_001395394.1:p.Ile254Val missense NM_001408466.1:c.760A>G NP_001395395.1:p.Ile254Val missense NM_001408467.1:c.760A>G NP_001395396.1:p.Ile254Val missense NM_001408468.1:c.760A>G NP_001395397.1:p.Ile254Val missense NM_001408469.1:c.760A>G NP_001395398.1:p.Ile254Val missense NM_001408470.1:c.757A>G NP_001395399.1:p.Ile253Val missense NM_001408472.1:c.901A>G NP_001395401.1:p.Ile301Val missense NM_001408473.1:c.901A>G NP_001395402.1:p.Ile301Val missense NM_001408474.1:c.703A>G NP_001395403.1:p.Ile235Val missense NM_001408475.1:c.700A>G NP_001395404.1:p.Ile234Val missense NM_001408476.1:c.703A>G NP_001395405.1:p.Ile235Val missense NM_001408478.1:c.694A>G NP_001395407.1:p.Ile232Val missense NM_001408479.1:c.694A>G NP_001395408.1:p.Ile232Val missense NM_001408480.1:c.694A>G NP_001395409.1:p.Ile232Val missense NM_001408481.1:c.694A>G NP_001395410.1:p.Ile232Val missense NM_001408482.1:c.694A>G NP_001395411.1:p.Ile232Val missense NM_001408483.1:c.694A>G NP_001395412.1:p.Ile232Val missense NM_001408484.1:c.694A>G NP_001395413.1:p.Ile232Val missense NM_001408485.1:c.694A>G NP_001395414.1:p.Ile232Val missense NM_001408489.1:c.691A>G NP_001395418.1:p.Ile231Val missense NM_001408490.1:c.691A>G NP_001395419.1:p.Ile231Val missense NM_001408491.1:c.691A>G NP_001395420.1:p.Ile231Val missense NM_001408492.1:c.691A>G NP_001395421.1:p.Ile231Val missense NM_001408493.1:c.691A>G NP_001395422.1:p.Ile231Val missense NM_001408494.1:c.664A>G NP_001395423.1:p.Ile222Val missense NM_001408495.1:c.661A>G NP_001395424.1:p.Ile221Val missense NM_001408496.1:c.640A>G NP_001395425.1:p.Ile214Val missense NM_001408497.1:c.640A>G NP_001395426.1:p.Ile214Val missense NM_001408498.1:c.640A>G NP_001395427.1:p.Ile214Val missense NM_001408499.1:c.640A>G NP_001395428.1:p.Ile214Val missense NM_001408500.1:c.640A>G NP_001395429.1:p.Ile214Val missense NM_001408501.1:c.640A>G NP_001395430.1:p.Ile214Val missense NM_001408502.1:c.571A>G NP_001395431.1:p.Ile191Val missense NM_001408503.1:c.637A>G NP_001395432.1:p.Ile213Val missense NM_001408504.1:c.637A>G NP_001395433.1:p.Ile213Val missense NM_001408505.1:c.637A>G NP_001395434.1:p.Ile213Val missense NM_001408506.1:c.577A>G NP_001395435.1:p.Ile193Val missense NM_001408507.1:c.574A>G NP_001395436.1:p.Ile192Val missense NM_001408508.1:c.565A>G NP_001395437.1:p.Ile189Val missense NM_001408509.1:c.565A>G NP_001395438.1:p.Ile189Val missense NM_001408510.1:c.523A>G NP_001395439.1:p.Ile175Val missense NM_001408511.1:c.520A>G NP_001395440.1:p.Ile174Val missense NM_001408512.1:c.400A>G NP_001395441.1:p.Ile134Val missense NM_001408513.1:c.691A>G NP_001395442.1:p.Ile231Val missense NM_001408514.1:c.694A>G NP_001395443.1:p.Ile232Val missense NM_007297.4:c.4072A>G NP_009228.2:p.Ile1358Val missense NM_007298.4:c.904A>G NP_009229.2:p.Ile302Val missense NM_007299.4:c.904A>G NP_009230.2:p.Ile302Val missense NM_007300.4:c.4213A>G NP_009231.2:p.Ile1405Val missense NM_007304.2:c.904A>G NP_009235.2:p.Ile302Val missense NR_027676.2:n.4390A>G non-coding transcript variant NC_000017.11:g.43082548T>C NC_000017.10:g.41234565T>C NG_005905.2:g.135436A>G LRG_292:g.135436A>G LRG_292t1:c.4213A>G LRG_292p1:p.Ile1405Val U14680.1:n.4332A>G - Protein change
- I1405V, I1358V, I302V, I1236V, I1315V, I1316V, I1334V, I1338V, I1357V, I1364V, I1378V, I175V, I213V, I214V, I232V, I235V, I253V, I254V, I257V, I262V, I276V, I1277V, I1293V, I1317V, I1337V, I134V, I1379V, I1403V, I1404V, I221V, I260V, I275V, I537V, I1109V, I1292V, I1294V, I1335V, I1362V, I1363V, I1377V, I1401V, I1278V, I1333V, I1356V, I192V, I193V, I222V, I231V, I261V, I263V, I299V, I300V, I174V, I189V, I191V, I234V, I255V, I301V, I536V
- Other names
-
4332A>G
- Canonical SPDI
- NC_000017.11:43082547:T:C
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
- 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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Aug 15, 2023 | RCV000031156.17 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 15, 2021 | RCV000444773.11 | |
| Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 28, 2019 | RCV000565302.15 | |
| Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 18, 2020 | RCV000679696.17 | |
| Likely benign (1) |
criteria provided, single submitter
|
Oct 3, 2023 | RCV001078939.14 |
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. |
|
|---|---|---|---|---|---|
|
Likely benign
(Oct 03, 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: SCV000076503.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
|
|
|
Likely benign
(Mar 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000668387.5
First in ClinVar: Jan 01, 2018 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)
|
|
|
Uncertain significance
(Sep 25, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785577.2
First in ClinVar: May 27, 2015 Last updated: May 27, 2015 |
|
|
|
Likely benign
(Oct 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000806947.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
|
|
|
Likely benign
(Feb 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000516168.6
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 12080089, 15235020, 18259752, 15385441, 17924331)
|
|
|
Likely Benign
(Aug 15, 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: SCV004817692.1
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)
|
Number of individuals with the variant: 5
|
|
|
Likely benign
(Jan 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916735.2
First in ClinVar: Jun 02, 2019 Last updated: Feb 12, 2021 |
Comment:
Variant summary: BRCA1 c.4213A>G (p.Ile1405Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: BRCA1 c.4213A>G (p.Ile1405Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 348962 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.3e-05 vs 0.001), allowing no conclusion about variant significance. c.4213A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Easton_2007, Shimelis_2017, Santonocito_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function by measuring transcriptional activity in a yeast-based system, and when combined with computational algorithms predicting variant effects, classified the variant as "likely not pathogenic" (e.g. Woods_2016, Fernandes_2019). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=5) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Likely benign
(Jan 04, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000683163.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
|
|
|
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: SCV000145031.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 2
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
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: SCV001550385.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRCA1 p.Ile1405Val variant was identified in the literature; however, the frequency of this variant in an affected population was not provided (Abkevich 2004, Easton … (more)
The BRCA1 p.Ile1405Val variant was identified in the literature; however, the frequency of this variant in an affected population was not provided (Abkevich 2004, Easton 2007). The variant was also identified in dbSNP (ID: rs80357353) as "With other allele", ClinVar (classified as benign by SCRP; as likely benign by Invitae, Ambry Genetics, GeneDx, and two other submitters; and as uncertain significance by Counsyl and BIC), COGR, MutDB , LOVD 3.0 (2x ), UMD-LSDB (2x unclassified variant), and BIC Database (2x with unknown significance). The variant was not identified in Cosmic, ARUP Laboratories, or Zhejiang University Database. The variant was identified in control databases in 15 of 246146 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111622 chromosomes (freq: 0.00003) and South Asian in 12 of 30782 chromosomes (freq: 0.0004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ile1405 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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)
|
|
|
Benign
(Apr 25, 2011)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000053756.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant is associated with the following publications: (PMID: 12080089, 15235020, 18259752, 15385441, 17924331)
Comment:
Variant summary: BRCA1 c.4213A>G (p.Ile1405Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 348962 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.3e-05 vs 0.001), allowing no conclusion about variant significance. c.4213A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Easton_2007, Shimelis_2017, Santonocito_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function by measuring transcriptional activity in a yeast-based system, and when combined with computational algorithms predicting variant effects, classified the variant as "likely not pathogenic" (e.g. Woods_2016, Fernandes_2019). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=5) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
The BRCA1 p.Ile1405Val variant was identified in the literature; however, the frequency of this variant in an affected population was not provided (Abkevich 2004, Easton 2007). The variant was also identified in dbSNP (ID: rs80357353) as "With other allele", ClinVar (classified as benign by SCRP; as likely benign by Invitae, Ambry Genetics, GeneDx, and two other submitters; and as uncertain significance by Counsyl and BIC), COGR, MutDB , LOVD 3.0 (2x ), UMD-LSDB (2x unclassified variant), and BIC Database (2x with unknown significance). The variant was not identified in Cosmic, ARUP Laboratories, or Zhejiang University Database. The variant was identified in control databases in 15 of 246146 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111622 chromosomes (freq: 0.00003) and South Asian in 12 of 30782 chromosomes (freq: 0.0004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ile1405 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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
| 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 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 associated with the following publications: (PMID: 12080089, 15235020, 18259752, 15385441, 17924331)
Comment:
Variant summary: BRCA1 c.4213A>G (p.Ile1405Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 348962 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.3e-05 vs 0.001), allowing no conclusion about variant significance. c.4213A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Easton_2007, Shimelis_2017, Santonocito_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function by measuring transcriptional activity in a yeast-based system, and when combined with computational algorithms predicting variant effects, classified the variant as "likely not pathogenic" (e.g. Woods_2016, Fernandes_2019). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=5) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
The BRCA1 p.Ile1405Val variant was identified in the literature; however, the frequency of this variant in an affected population was not provided (Abkevich 2004, Easton 2007). The variant was also identified in dbSNP (ID: rs80357353) as "With other allele", ClinVar (classified as benign by SCRP; as likely benign by Invitae, Ambry Genetics, GeneDx, and two other submitters; and as uncertain significance by Counsyl and BIC), COGR, MutDB , LOVD 3.0 (2x ), UMD-LSDB (2x unclassified variant), and BIC Database (2x with unknown significance). The variant was not identified in Cosmic, ARUP Laboratories, or Zhejiang University Database. The variant was identified in control databases in 15 of 246146 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111622 chromosomes (freq: 0.00003) and South Asian in 12 of 30782 chromosomes (freq: 0.0004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ile1405 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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 |
|---|---|---|---|---|
| Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. | Santonocito C | Cancers | 2020 | PMID: 32438681 |
| 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 |
| Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
| BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer. | Shimelis H | Cancer research | 2017 | PMID: 28283652 |
| Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. | Woods NT | NPJ genomic medicine | 2016 | PMID: 28781887 |
| BRCA1 transcriptional activity is enhanced by interactions between its AD1 domain and AhR. | Kang HJ | Cancer chemotherapy and pharmacology | 2008 | PMID: 18259752 |
| A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. | Easton DF | American journal of human genetics | 2007 | PMID: 17924331 |
| Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. | Abkevich V | Journal of medical genetics | 2004 | PMID: 15235020 |
| JunB potentiates function of BRCA1 activation domain 1 (AD1) through a coiled-coil-mediated interaction. | Hu YF | Genes & development | 2002 | PMID: 12080089 |
| The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
Text-mined citations for rs80357353 ...
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.