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.1397G>A (p.Arg466Gln)
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.
(15)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(2); Likely benign(6)
Uncertain significance(4); Benign(2); Likely benign(6)
15
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.1397G>A (p.Arg466Gln)
Variation ID: 91552 Accession: VCV000091552.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43094134 (GRCh38) [ NCBI UCSC ] 17: 41246151 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 27, 2014 Sep 16, 2024 May 28, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.1397G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Arg466Gln missense NM_001407571.1:c.1184G>A NP_001394500.1:p.Arg395Gln missense NM_001407581.1:c.1397G>A NP_001394510.1:p.Arg466Gln missense NM_001407582.1:c.1397G>A NP_001394511.1:p.Arg466Gln missense NM_001407583.1:c.1397G>A NP_001394512.1:p.Arg466Gln missense NM_001407585.1:c.1397G>A NP_001394514.1:p.Arg466Gln missense NM_001407587.1:c.1394G>A NP_001394516.1:p.Arg465Gln missense NM_001407590.1:c.1394G>A NP_001394519.1:p.Arg465Gln missense NM_001407591.1:c.1394G>A NP_001394520.1:p.Arg465Gln missense NM_001407593.1:c.1397G>A NP_001394522.1:p.Arg466Gln missense NM_001407594.1:c.1397G>A NP_001394523.1:p.Arg466Gln missense NM_001407596.1:c.1397G>A NP_001394525.1:p.Arg466Gln missense NM_001407597.1:c.1397G>A NP_001394526.1:p.Arg466Gln missense NM_001407598.1:c.1397G>A NP_001394527.1:p.Arg466Gln missense NM_001407602.1:c.1397G>A NP_001394531.1:p.Arg466Gln missense NM_001407603.1:c.1397G>A NP_001394532.1:p.Arg466Gln missense NM_001407605.1:c.1397G>A NP_001394534.1:p.Arg466Gln missense NM_001407610.1:c.1394G>A NP_001394539.1:p.Arg465Gln missense NM_001407611.1:c.1394G>A NP_001394540.1:p.Arg465Gln missense NM_001407612.1:c.1394G>A NP_001394541.1:p.Arg465Gln missense NM_001407613.1:c.1394G>A NP_001394542.1:p.Arg465Gln missense NM_001407614.1:c.1394G>A NP_001394543.1:p.Arg465Gln missense NM_001407615.1:c.1394G>A NP_001394544.1:p.Arg465Gln missense NM_001407616.1:c.1397G>A NP_001394545.1:p.Arg466Gln missense NM_001407617.1:c.1397G>A NP_001394546.1:p.Arg466Gln missense NM_001407618.1:c.1397G>A NP_001394547.1:p.Arg466Gln missense NM_001407619.1:c.1397G>A NP_001394548.1:p.Arg466Gln missense NM_001407620.1:c.1397G>A NP_001394549.1:p.Arg466Gln missense NM_001407621.1:c.1397G>A NP_001394550.1:p.Arg466Gln missense NM_001407622.1:c.1397G>A NP_001394551.1:p.Arg466Gln missense NM_001407623.1:c.1397G>A NP_001394552.1:p.Arg466Gln missense NM_001407624.1:c.1397G>A NP_001394553.1:p.Arg466Gln missense NM_001407625.1:c.1397G>A NP_001394554.1:p.Arg466Gln missense NM_001407626.1:c.1397G>A NP_001394555.1:p.Arg466Gln missense NM_001407627.1:c.1394G>A NP_001394556.1:p.Arg465Gln missense NM_001407628.1:c.1394G>A NP_001394557.1:p.Arg465Gln missense NM_001407629.1:c.1394G>A NP_001394558.1:p.Arg465Gln missense NM_001407630.1:c.1394G>A NP_001394559.1:p.Arg465Gln missense NM_001407631.1:c.1394G>A NP_001394560.1:p.Arg465Gln missense NM_001407632.1:c.1394G>A NP_001394561.1:p.Arg465Gln missense NM_001407633.1:c.1394G>A NP_001394562.1:p.Arg465Gln missense NM_001407634.1:c.1394G>A NP_001394563.1:p.Arg465Gln missense NM_001407635.1:c.1394G>A NP_001394564.1:p.Arg465Gln missense NM_001407636.1:c.1394G>A NP_001394565.1:p.Arg465Gln missense NM_001407637.1:c.1394G>A NP_001394566.1:p.Arg465Gln missense NM_001407638.1:c.1394G>A NP_001394567.1:p.Arg465Gln missense NM_001407639.1:c.1397G>A NP_001394568.1:p.Arg466Gln missense NM_001407640.1:c.1397G>A NP_001394569.1:p.Arg466Gln missense NM_001407641.1:c.1397G>A NP_001394570.1:p.Arg466Gln missense NM_001407642.1:c.1397G>A NP_001394571.1:p.Arg466Gln missense NM_001407644.1:c.1394G>A NP_001394573.1:p.Arg465Gln missense NM_001407645.1:c.1394G>A NP_001394574.1:p.Arg465Gln missense NM_001407646.1:c.1388G>A NP_001394575.1:p.Arg463Gln missense NM_001407647.1:c.1388G>A NP_001394576.1:p.Arg463Gln missense NM_001407648.1:c.1274G>A NP_001394577.1:p.Arg425Gln missense NM_001407649.1:c.1271G>A NP_001394578.1:p.Arg424Gln missense NM_001407652.1:c.1397G>A NP_001394581.1:p.Arg466Gln missense NM_001407653.1:c.1319G>A NP_001394582.1:p.Arg440Gln missense NM_001407654.1:c.1319G>A NP_001394583.1:p.Arg440Gln missense NM_001407655.1:c.1319G>A NP_001394584.1:p.Arg440Gln missense NM_001407656.1:c.1319G>A NP_001394585.1:p.Arg440Gln missense NM_001407657.1:c.1319G>A NP_001394586.1:p.Arg440Gln missense NM_001407658.1:c.1319G>A NP_001394587.1:p.Arg440Gln missense NM_001407659.1:c.1316G>A NP_001394588.1:p.Arg439Gln missense NM_001407660.1:c.1316G>A NP_001394589.1:p.Arg439Gln missense NM_001407661.1:c.1316G>A NP_001394590.1:p.Arg439Gln missense NM_001407662.1:c.1316G>A NP_001394591.1:p.Arg439Gln missense NM_001407663.1:c.1319G>A NP_001394592.1:p.Arg440Gln missense NM_001407664.1:c.1274G>A NP_001394593.1:p.Arg425Gln missense NM_001407665.1:c.1274G>A NP_001394594.1:p.Arg425Gln missense NM_001407666.1:c.1274G>A NP_001394595.1:p.Arg425Gln missense NM_001407667.1:c.1274G>A NP_001394596.1:p.Arg425Gln missense NM_001407668.1:c.1274G>A NP_001394597.1:p.Arg425Gln missense NM_001407669.1:c.1274G>A NP_001394598.1:p.Arg425Gln missense NM_001407670.1:c.1271G>A NP_001394599.1:p.Arg424Gln missense NM_001407671.1:c.1271G>A NP_001394600.1:p.Arg424Gln missense NM_001407672.1:c.1271G>A NP_001394601.1:p.Arg424Gln missense NM_001407673.1:c.1271G>A NP_001394602.1:p.Arg424Gln missense NM_001407674.1:c.1274G>A NP_001394603.1:p.Arg425Gln missense NM_001407675.1:c.1274G>A NP_001394604.1:p.Arg425Gln missense NM_001407676.1:c.1274G>A NP_001394605.1:p.Arg425Gln missense NM_001407677.1:c.1274G>A NP_001394606.1:p.Arg425Gln missense NM_001407678.1:c.1274G>A NP_001394607.1:p.Arg425Gln missense NM_001407679.1:c.1274G>A NP_001394608.1:p.Arg425Gln missense NM_001407680.1:c.1274G>A NP_001394609.1:p.Arg425Gln missense NM_001407681.1:c.1274G>A NP_001394610.1:p.Arg425Gln missense NM_001407682.1:c.1274G>A NP_001394611.1:p.Arg425Gln missense NM_001407683.1:c.1274G>A NP_001394612.1:p.Arg425Gln missense NM_001407684.1:c.1397G>A NP_001394613.1:p.Arg466Gln missense NM_001407685.1:c.1271G>A NP_001394614.1:p.Arg424Gln missense NM_001407686.1:c.1271G>A NP_001394615.1:p.Arg424Gln missense NM_001407687.1:c.1271G>A NP_001394616.1:p.Arg424Gln missense NM_001407688.1:c.1271G>A NP_001394617.1:p.Arg424Gln missense NM_001407689.1:c.1271G>A NP_001394618.1:p.Arg424Gln missense NM_001407690.1:c.1271G>A NP_001394619.1:p.Arg424Gln missense NM_001407691.1:c.1271G>A NP_001394620.1:p.Arg424Gln missense NM_001407692.1:c.1256G>A NP_001394621.1:p.Arg419Gln missense NM_001407694.1:c.1256G>A NP_001394623.1:p.Arg419Gln missense NM_001407695.1:c.1256G>A NP_001394624.1:p.Arg419Gln missense NM_001407696.1:c.1256G>A NP_001394625.1:p.Arg419Gln missense NM_001407697.1:c.1256G>A NP_001394626.1:p.Arg419Gln missense NM_001407698.1:c.1256G>A NP_001394627.1:p.Arg419Gln missense NM_001407724.1:c.1256G>A NP_001394653.1:p.Arg419Gln missense NM_001407725.1:c.1256G>A NP_001394654.1:p.Arg419Gln missense NM_001407726.1:c.1256G>A NP_001394655.1:p.Arg419Gln missense NM_001407727.1:c.1256G>A NP_001394656.1:p.Arg419Gln missense NM_001407728.1:c.1256G>A NP_001394657.1:p.Arg419Gln missense NM_001407729.1:c.1256G>A NP_001394658.1:p.Arg419Gln missense NM_001407730.1:c.1256G>A NP_001394659.1:p.Arg419Gln missense NM_001407731.1:c.1256G>A NP_001394660.1:p.Arg419Gln missense NM_001407732.1:c.1256G>A NP_001394661.1:p.Arg419Gln missense NM_001407733.1:c.1256G>A NP_001394662.1:p.Arg419Gln missense NM_001407734.1:c.1256G>A NP_001394663.1:p.Arg419Gln missense NM_001407735.1:c.1256G>A NP_001394664.1:p.Arg419Gln missense NM_001407736.1:c.1256G>A NP_001394665.1:p.Arg419Gln missense NM_001407737.1:c.1256G>A NP_001394666.1:p.Arg419Gln missense NM_001407738.1:c.1256G>A NP_001394667.1:p.Arg419Gln missense NM_001407739.1:c.1256G>A NP_001394668.1:p.Arg419Gln missense NM_001407740.1:c.1253G>A NP_001394669.1:p.Arg418Gln missense NM_001407741.1:c.1253G>A NP_001394670.1:p.Arg418Gln missense NM_001407742.1:c.1253G>A NP_001394671.1:p.Arg418Gln missense NM_001407743.1:c.1253G>A NP_001394672.1:p.Arg418Gln missense NM_001407744.1:c.1253G>A NP_001394673.1:p.Arg418Gln missense NM_001407745.1:c.1253G>A NP_001394674.1:p.Arg418Gln missense NM_001407746.1:c.1253G>A NP_001394675.1:p.Arg418Gln missense NM_001407747.1:c.1253G>A NP_001394676.1:p.Arg418Gln missense NM_001407748.1:c.1253G>A NP_001394677.1:p.Arg418Gln missense NM_001407749.1:c.1253G>A NP_001394678.1:p.Arg418Gln missense NM_001407750.1:c.1256G>A NP_001394679.1:p.Arg419Gln missense NM_001407751.1:c.1256G>A NP_001394680.1:p.Arg419Gln missense NM_001407752.1:c.1256G>A NP_001394681.1:p.Arg419Gln missense NM_001407838.1:c.1253G>A NP_001394767.1:p.Arg418Gln missense NM_001407839.1:c.1253G>A NP_001394768.1:p.Arg418Gln missense NM_001407841.1:c.1253G>A NP_001394770.1:p.Arg418Gln missense NM_001407842.1:c.1253G>A NP_001394771.1:p.Arg418Gln missense NM_001407843.1:c.1253G>A NP_001394772.1:p.Arg418Gln missense NM_001407844.1:c.1253G>A NP_001394773.1:p.Arg418Gln missense NM_001407845.1:c.1253G>A NP_001394774.1:p.Arg418Gln missense NM_001407846.1:c.1253G>A NP_001394775.1:p.Arg418Gln missense NM_001407847.1:c.1253G>A NP_001394776.1:p.Arg418Gln missense NM_001407848.1:c.1253G>A NP_001394777.1:p.Arg418Gln missense NM_001407849.1:c.1253G>A NP_001394778.1:p.Arg418Gln missense NM_001407850.1:c.1256G>A NP_001394779.1:p.Arg419Gln missense NM_001407851.1:c.1256G>A NP_001394780.1:p.Arg419Gln missense NM_001407852.1:c.1256G>A NP_001394781.1:p.Arg419Gln missense NM_001407853.1:c.1184G>A NP_001394782.1:p.Arg395Gln missense NM_001407854.1:c.1397G>A NP_001394783.1:p.Arg466Gln missense NM_001407858.1:c.1397G>A NP_001394787.1:p.Arg466Gln missense NM_001407859.1:c.1397G>A NP_001394788.1:p.Arg466Gln missense NM_001407860.1:c.1394G>A NP_001394789.1:p.Arg465Gln missense NM_001407861.1:c.1394G>A NP_001394790.1:p.Arg465Gln missense NM_001407862.1:c.1196G>A NP_001394791.1:p.Arg399Gln missense NM_001407863.1:c.1274G>A NP_001394792.1:p.Arg425Gln missense NM_001407874.1:c.1193G>A NP_001394803.1:p.Arg398Gln missense NM_001407875.1:c.1193G>A NP_001394804.1:p.Arg398Gln missense NM_001407879.1:c.1187G>A NP_001394808.1:p.Arg396Gln missense NM_001407881.1:c.1187G>A NP_001394810.1:p.Arg396Gln missense NM_001407882.1:c.1187G>A NP_001394811.1:p.Arg396Gln missense NM_001407884.1:c.1187G>A NP_001394813.1:p.Arg396Gln missense NM_001407885.1:c.1187G>A NP_001394814.1:p.Arg396Gln missense NM_001407886.1:c.1187G>A NP_001394815.1:p.Arg396Gln missense NM_001407887.1:c.1187G>A NP_001394816.1:p.Arg396Gln missense NM_001407889.1:c.1187G>A NP_001394818.1:p.Arg396Gln missense NM_001407894.1:c.1184G>A NP_001394823.1:p.Arg395Gln missense NM_001407895.1:c.1184G>A NP_001394824.1:p.Arg395Gln missense NM_001407896.1:c.1184G>A NP_001394825.1:p.Arg395Gln missense NM_001407897.1:c.1184G>A NP_001394826.1:p.Arg395Gln missense NM_001407898.1:c.1184G>A NP_001394827.1:p.Arg395Gln missense NM_001407899.1:c.1184G>A NP_001394828.1:p.Arg395Gln missense NM_001407900.1:c.1187G>A NP_001394829.1:p.Arg396Gln missense NM_001407902.1:c.1187G>A NP_001394831.1:p.Arg396Gln missense NM_001407904.1:c.1187G>A NP_001394833.1:p.Arg396Gln missense NM_001407906.1:c.1187G>A NP_001394835.1:p.Arg396Gln missense NM_001407907.1:c.1187G>A NP_001394836.1:p.Arg396Gln missense NM_001407908.1:c.1187G>A NP_001394837.1:p.Arg396Gln missense NM_001407909.1:c.1187G>A NP_001394838.1:p.Arg396Gln missense NM_001407910.1:c.1187G>A NP_001394839.1:p.Arg396Gln missense NM_001407915.1:c.1184G>A NP_001394844.1:p.Arg395Gln missense NM_001407916.1:c.1184G>A NP_001394845.1:p.Arg395Gln missense NM_001407917.1:c.1184G>A NP_001394846.1:p.Arg395Gln missense NM_001407918.1:c.1184G>A NP_001394847.1:p.Arg395Gln missense NM_001407919.1:c.1274G>A NP_001394848.1:p.Arg425Gln missense NM_001407920.1:c.1133G>A NP_001394849.1:p.Arg378Gln missense NM_001407921.1:c.1133G>A NP_001394850.1:p.Arg378Gln missense NM_001407922.1:c.1133G>A NP_001394851.1:p.Arg378Gln missense NM_001407923.1:c.1133G>A NP_001394852.1:p.Arg378Gln missense NM_001407924.1:c.1133G>A NP_001394853.1:p.Arg378Gln missense NM_001407925.1:c.1133G>A NP_001394854.1:p.Arg378Gln missense NM_001407926.1:c.1133G>A NP_001394855.1:p.Arg378Gln missense NM_001407927.1:c.1133G>A NP_001394856.1:p.Arg378Gln missense NM_001407928.1:c.1133G>A NP_001394857.1:p.Arg378Gln missense NM_001407929.1:c.1133G>A NP_001394858.1:p.Arg378Gln missense NM_001407930.1:c.1130G>A NP_001394859.1:p.Arg377Gln missense NM_001407931.1:c.1130G>A NP_001394860.1:p.Arg377Gln missense NM_001407932.1:c.1130G>A NP_001394861.1:p.Arg377Gln missense NM_001407933.1:c.1133G>A NP_001394862.1:p.Arg378Gln missense NM_001407934.1:c.1130G>A NP_001394863.1:p.Arg377Gln missense NM_001407935.1:c.1133G>A NP_001394864.1:p.Arg378Gln missense NM_001407936.1:c.1130G>A NP_001394865.1:p.Arg377Gln missense NM_001407937.1:c.1274G>A NP_001394866.1:p.Arg425Gln missense NM_001407938.1:c.1274G>A NP_001394867.1:p.Arg425Gln missense NM_001407939.1:c.1274G>A NP_001394868.1:p.Arg425Gln missense NM_001407940.1:c.1271G>A NP_001394869.1:p.Arg424Gln missense NM_001407941.1:c.1271G>A NP_001394870.1:p.Arg424Gln missense NM_001407942.1:c.1256G>A NP_001394871.1:p.Arg419Gln missense NM_001407943.1:c.1253G>A NP_001394872.1:p.Arg418Gln missense NM_001407944.1:c.1256G>A NP_001394873.1:p.Arg419Gln missense NM_001407945.1:c.1256G>A NP_001394874.1:p.Arg419Gln missense NM_001407946.1:c.1064G>A NP_001394875.1:p.Arg355Gln missense NM_001407947.1:c.1064G>A NP_001394876.1:p.Arg355Gln missense NM_001407948.1:c.1064G>A NP_001394877.1:p.Arg355Gln missense NM_001407949.1:c.1064G>A NP_001394878.1:p.Arg355Gln missense NM_001407950.1:c.1064G>A NP_001394879.1:p.Arg355Gln missense NM_001407951.1:c.1064G>A NP_001394880.1:p.Arg355Gln missense NM_001407952.1:c.1064G>A NP_001394881.1:p.Arg355Gln missense NM_001407953.1:c.1064G>A NP_001394882.1:p.Arg355Gln missense NM_001407954.1:c.1061G>A NP_001394883.1:p.Arg354Gln missense NM_001407955.1:c.1061G>A NP_001394884.1:p.Arg354Gln missense NM_001407956.1:c.1061G>A NP_001394885.1:p.Arg354Gln missense NM_001407957.1:c.1064G>A NP_001394886.1:p.Arg355Gln missense NM_001407958.1:c.1061G>A NP_001394887.1:p.Arg354Gln missense NM_001407959.1:c.1016G>A NP_001394888.1:p.Arg339Gln missense NM_001407960.1:c.1016G>A NP_001394889.1:p.Arg339Gln missense NM_001407962.1:c.1013G>A NP_001394891.1:p.Arg338Gln missense NM_001407963.1:c.1016G>A NP_001394892.1:p.Arg339Gln missense NM_001407964.1:c.1253G>A NP_001394893.1:p.Arg418Gln missense NM_001407965.1:c.893G>A NP_001394894.1:p.Arg298Gln missense NM_001407966.1:c.509G>A NP_001394895.1:p.Arg170Gln missense NM_001407967.1:c.509G>A NP_001394896.1:p.Arg170Gln missense NM_001407968.1:c.787+610G>A intron variant NM_001407969.1:c.787+610G>A intron variant NM_001407970.1:c.787+610G>A intron variant NM_001407971.1:c.787+610G>A intron variant NM_001407972.1:c.784+610G>A intron variant NM_001407973.1:c.787+610G>A intron variant NM_001407974.1:c.787+610G>A intron variant NM_001407975.1:c.787+610G>A intron variant NM_001407976.1:c.787+610G>A intron variant NM_001407977.1:c.787+610G>A intron variant NM_001407978.1:c.787+610G>A intron variant NM_001407979.1:c.787+610G>A intron variant NM_001407980.1:c.787+610G>A intron variant NM_001407981.1:c.787+610G>A intron variant NM_001407982.1:c.787+610G>A intron variant NM_001407983.1:c.787+610G>A intron variant NM_001407984.1:c.784+610G>A intron variant NM_001407985.1:c.784+610G>A intron variant NM_001407986.1:c.784+610G>A intron variant NM_001407990.1:c.787+610G>A intron variant NM_001407991.1:c.784+610G>A intron variant NM_001407992.1:c.784+610G>A intron variant NM_001407993.1:c.787+610G>A intron variant NM_001408392.1:c.784+610G>A intron variant NM_001408396.1:c.784+610G>A intron variant NM_001408397.1:c.784+610G>A intron variant NM_001408398.1:c.784+610G>A intron variant NM_001408399.1:c.784+610G>A intron variant NM_001408400.1:c.784+610G>A intron variant NM_001408401.1:c.784+610G>A intron variant NM_001408402.1:c.784+610G>A intron variant NM_001408403.1:c.787+610G>A intron variant NM_001408404.1:c.787+610G>A intron variant NM_001408406.1:c.790+607G>A intron variant NM_001408407.1:c.784+610G>A intron variant NM_001408408.1:c.778+610G>A intron variant NM_001408409.1:c.709+610G>A intron variant NM_001408410.1:c.646+610G>A intron variant NM_001408411.1:c.709+610G>A intron variant NM_001408412.1:c.709+610G>A intron variant NM_001408413.1:c.706+610G>A intron variant NM_001408414.1:c.709+610G>A intron variant NM_001408415.1:c.709+610G>A intron variant NM_001408416.1:c.706+610G>A intron variant NM_001408418.1:c.670+1712G>A intron variant NM_001408419.1:c.670+1712G>A intron variant NM_001408420.1:c.670+1712G>A intron variant NM_001408421.1:c.667+1712G>A intron variant NM_001408422.1:c.670+1712G>A intron variant NM_001408423.1:c.670+1712G>A intron variant NM_001408424.1:c.667+1712G>A intron variant NM_001408425.1:c.664+610G>A intron variant NM_001408426.1:c.664+610G>A intron variant NM_001408427.1:c.664+610G>A intron variant NM_001408428.1:c.664+610G>A intron variant NM_001408429.1:c.664+610G>A intron variant NM_001408430.1:c.664+610G>A intron variant NM_001408431.1:c.667+1712G>A intron variant NM_001408432.1:c.661+610G>A intron variant NM_001408433.1:c.661+610G>A intron variant NM_001408434.1:c.661+610G>A intron variant NM_001408435.1:c.661+610G>A intron variant NM_001408436.1:c.664+610G>A intron variant NM_001408437.1:c.664+610G>A intron variant NM_001408438.1:c.664+610G>A intron variant NM_001408439.1:c.664+610G>A intron variant NM_001408440.1:c.664+610G>A intron variant NM_001408441.1:c.664+610G>A intron variant NM_001408442.1:c.664+610G>A intron variant NM_001408443.1:c.664+610G>A intron variant NM_001408444.1:c.664+610G>A intron variant NM_001408445.1:c.661+610G>A intron variant NM_001408446.1:c.661+610G>A intron variant NM_001408447.1:c.661+610G>A intron variant NM_001408448.1:c.661+610G>A intron variant NM_001408450.1:c.661+610G>A intron variant NM_001408451.1:c.652+610G>A intron variant NM_001408452.1:c.646+610G>A intron variant NM_001408453.1:c.646+610G>A intron variant NM_001408454.1:c.646+610G>A intron variant NM_001408455.1:c.646+610G>A intron variant NM_001408456.1:c.646+610G>A intron variant NM_001408457.1:c.646+610G>A intron variant NM_001408458.1:c.646+610G>A intron variant NM_001408459.1:c.646+610G>A intron variant NM_001408460.1:c.646+610G>A intron variant NM_001408461.1:c.646+610G>A intron variant NM_001408462.1:c.643+610G>A intron variant NM_001408463.1:c.643+610G>A intron variant NM_001408464.1:c.643+610G>A intron variant NM_001408465.1:c.643+610G>A intron variant NM_001408466.1:c.646+610G>A intron variant NM_001408467.1:c.646+610G>A intron variant NM_001408468.1:c.643+610G>A intron variant NM_001408469.1:c.646+610G>A intron variant NM_001408470.1:c.643+610G>A intron variant NM_001408472.1:c.787+610G>A intron variant NM_001408473.1:c.784+610G>A intron variant NM_001408474.1:c.586+610G>A intron variant NM_001408475.1:c.583+610G>A intron variant NM_001408476.1:c.586+610G>A intron variant NM_001408478.1:c.577+610G>A intron variant NM_001408479.1:c.577+610G>A intron variant NM_001408480.1:c.577+610G>A intron variant NM_001408481.1:c.577+610G>A intron variant NM_001408482.1:c.577+610G>A intron variant NM_001408483.1:c.577+610G>A intron variant NM_001408484.1:c.577+610G>A intron variant NM_001408485.1:c.577+610G>A intron variant NM_001408489.1:c.577+610G>A intron variant NM_001408490.1:c.574+610G>A intron variant NM_001408491.1:c.574+610G>A intron variant NM_001408492.1:c.577+610G>A intron variant NM_001408493.1:c.574+610G>A intron variant NM_001408494.1:c.548-3102G>A intron variant NM_001408495.1:c.545-3102G>A intron variant NM_001408496.1:c.523+610G>A intron variant NM_001408497.1:c.523+610G>A intron variant NM_001408498.1:c.523+610G>A intron variant NM_001408499.1:c.523+610G>A intron variant NM_001408500.1:c.523+610G>A intron variant NM_001408501.1:c.523+610G>A intron variant NM_001408502.1:c.454+610G>A intron variant NM_001408503.1:c.520+610G>A intron variant NM_001408504.1:c.520+610G>A intron variant NM_001408505.1:c.520+610G>A intron variant NM_001408506.1:c.460+1712G>A intron variant NM_001408507.1:c.460+1712G>A intron variant NM_001408508.1:c.451+610G>A intron variant NM_001408509.1:c.451+610G>A intron variant NM_001408510.1:c.406+610G>A intron variant NM_001408511.1:c.404-3102G>A intron variant NM_001408512.1:c.283+610G>A intron variant NM_001408513.1:c.577+610G>A intron variant NM_001408514.1:c.577+610G>A intron variant NM_007297.4:c.1256G>A NP_009228.2:p.Arg419Gln missense NM_007298.4:c.787+610G>A intron variant NM_007299.4:c.787+610G>A intron variant NM_007300.4:c.1397G>A NP_009231.2:p.Arg466Gln missense NR_027676.1:n.1533G>A NC_000017.11:g.43094134C>T NC_000017.10:g.41246151C>T NG_005905.2:g.123850G>A LRG_292:g.123850G>A LRG_292t1:c.1397G>A LRG_292p1:p.Arg466Gln - Protein change
- R466Q, R419Q, R170Q, R354Q, R395Q, R396Q, R398Q, R424Q, R439Q, R440Q, R463Q, R338Q, R339Q, R355Q, R377Q, R425Q, R418Q, R465Q, R298Q, R378Q, R399Q
- Other names
-
p.R466Q:CGG>CAG
1516G>A
- Canonical SPDI
- NC_000017.11:43094133:C:T
-
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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00005
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13050 | 14856 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, single submitter
|
Nov 17, 2015 | RCV000077069.7 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Mar 23, 2023 | RCV000132262.12 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Sep 18, 2022 | RCV000159868.9 | |
| Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
May 28, 2024 | RCV000469966.14 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001354036.3 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Feb 6, 2023 | RCV001509546.11 |
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
(May 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000187345.7
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)
|
|
|
Uncertain significance
(Apr 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Department of Pathology and Molecular Medicine, Queen's University
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000588033.1 First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
|
|
|
Benign
(Nov 14, 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: SCV000911275.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
|
|
Uncertain significance
(Dec 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001716312.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
|
|
|
Likely benign
(Jul 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209923.13
First in ClinVar: Feb 24, 2015 Last updated: Aug 27, 2017 |
Comment:
This variant is associated with the following publications: (PMID: 28301460, 26941049)
|
|
|
Uncertain significance
(May 17, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002538021.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020
Comment:
The BRCA1 c.1397G>A (p.R466Q) variant has been reported in heterozygosity in at least one individual undergoing genetic testing for hereditary breast and ovarian cancer (PMID: … (more)
The BRCA1 c.1397G>A (p.R466Q) variant has been reported in heterozygosity in at least one individual undergoing genetic testing for hereditary breast and ovarian cancer (PMID: 30254663). This variant was observed in 4/34546 chromosomes in the Latino population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 91552). Computational analyses and evolutionary conservation data do not provide strong support for or against an impact on the protein, though these predictions have not been confirmed by functional studies. Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)
|
|
|
|
Likely benign
(Sep 18, 2022)
|
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: SCV000698859.3
First in ClinVar: Mar 17, 2018 Last updated: Nov 05, 2022 |
Comment:
Variant summary: BRCA1 c.1397G>A (p.Arg466Gln) results in a conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) of the encoded protein sequence. Five … (more)
Variant summary: BRCA1 c.1397G>A (p.Arg466Gln) results in a conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) of 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 2.4e-05 in 251102 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1397G>A has been reported in the literature as a VUS in settings of a family with breast cancer and in individuals undergoing germline BRCA1/2 cancer testing (example, Zuntini_2018. Kim_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Uncertain significance
(Nov 17, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487783.2
First in ClinVar: Sep 27, 2014 Last updated: Dec 24, 2022 |
|
|
|
Likely benign
(Mar 23, 2023)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV003851322.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Comment:
BRCA1 coldspot (exon 11 using historical exon numbering). Reclassification based on statistical prior probability
|
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
|
|
|
Likely benign
(Feb 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046110.2
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
|
|
|
Likely benign
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000549294.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
|
|
|
Benign
(May 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV005205736.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
|
|
|
Benign
(Mar 16, 2012)
|
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: SCV000108866.2
First in ClinVar: Dec 23, 2013 Last updated: Sep 27, 2014 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
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: SCV000591328.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The BRCA1 p.Arg466Gln variant was identified in dbSNP (ID: rs199540030) “With uncertain significance allele”, UMD (1X as an unclassified variant), GeneInsight COGR database (classified with … (more)
The BRCA1 p.Arg466Gln variant was identified in dbSNP (ID: rs199540030) “With uncertain significance allele”, UMD (1X as an unclassified variant), GeneInsight COGR database (classified with unknown significance by a clinical laboratory), and in the ClinVar database with conflicting classifications by three submitters (classified as benign by Sharing Clinical Reports Project, derived from Myriad reports; classified as likely benign by GeneDx; classified with uncertain significance by Ambry Genetics). The variant was identified in the 1000 Genomes project (1/5000 chromosomes, frequency 0.0002) and in the Exome Aggregation Consortium (ExAC) database (3/11576 Latino chromosomes, frequency: 0.00026; 3/66722 European (Non-Finnish) chromosomes, frequency: 0.00004); the presence of the variant at these low frequencies is not substantive enough to comment on the relationship of this variant to disease. The variant was not identified in the literature, nor was it identified in any other database searches including HGMD, LOVD, COSMIC, and BIC. The p.Arg466Gln residue is not conserved in mammals and other organisms, and four out of five 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. One of five in silico splicing prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the potential creation of a cryptic 3’ splice site downstream of the variant but this information is not very predictive of 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 unknown significance. (less)
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Benign
(Sep 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Department of Medical and Surgical Sciences, University of Bologna
Accession: SCV004228330.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
BS1(Supporting)+BS3(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
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Comment:
Comment:
This variant is associated with the following publications: (PMID: 28301460, 26941049)
Comment:
Variant summary: BRCA1 c.1397G>A (p.Arg466Gln) results in a conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) of 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 2.4e-05 in 251102 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1397G>A has been reported in the literature as a VUS in settings of a family with breast cancer and in individuals undergoing germline BRCA1/2 cancer testing (example, Zuntini_2018. Kim_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Comment:
The BRCA1 p.Arg466Gln variant was identified in dbSNP (ID: rs199540030) “With uncertain significance allele”, UMD (1X as an unclassified variant), GeneInsight COGR database (classified with unknown significance by a clinical laboratory), and in the ClinVar database with conflicting classifications by three submitters (classified as benign by Sharing Clinical Reports Project, derived from Myriad reports; classified as likely benign by GeneDx; classified with uncertain significance by Ambry Genetics). The variant was identified in the 1000 Genomes project (1/5000 chromosomes, frequency 0.0002) and in the Exome Aggregation Consortium (ExAC) database (3/11576 Latino chromosomes, frequency: 0.00026; 3/66722 European (Non-Finnish) chromosomes, frequency: 0.00004); the presence of the variant at these low frequencies is not substantive enough to comment on the relationship of this variant to disease. The variant was not identified in the literature, nor was it identified in any other database searches including HGMD, LOVD, COSMIC, and BIC. The p.Arg466Gln residue is not conserved in mammals and other organisms, and four out of five 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. One of five in silico splicing prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the potential creation of a cryptic 3’ splice site downstream of the variant but this information is not very predictive of 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 unknown significance.
Comment:
BS1(Supporting)+BS3(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
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: 28301460, 26941049)
Comment:
Variant summary: BRCA1 c.1397G>A (p.Arg466Gln) results in a conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) of 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 2.4e-05 in 251102 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1397G>A has been reported in the literature as a VUS in settings of a family with breast cancer and in individuals undergoing germline BRCA1/2 cancer testing (example, Zuntini_2018. Kim_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Comment:
The BRCA1 p.Arg466Gln variant was identified in dbSNP (ID: rs199540030) “With uncertain significance allele”, UMD (1X as an unclassified variant), GeneInsight COGR database (classified with unknown significance by a clinical laboratory), and in the ClinVar database with conflicting classifications by three submitters (classified as benign by Sharing Clinical Reports Project, derived from Myriad reports; classified as likely benign by GeneDx; classified with uncertain significance by Ambry Genetics). The variant was identified in the 1000 Genomes project (1/5000 chromosomes, frequency 0.0002) and in the Exome Aggregation Consortium (ExAC) database (3/11576 Latino chromosomes, frequency: 0.00026; 3/66722 European (Non-Finnish) chromosomes, frequency: 0.00004); the presence of the variant at these low frequencies is not substantive enough to comment on the relationship of this variant to disease. The variant was not identified in the literature, nor was it identified in any other database searches including HGMD, LOVD, COSMIC, and BIC. The p.Arg466Gln residue is not conserved in mammals and other organisms, and four out of five 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. One of five in silico splicing prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the potential creation of a cryptic 3’ splice site downstream of the variant but this information is not very predictive of 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 unknown significance.
Comment:
BS1(Supporting)+BS3(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic Signatures from Clinical Tumor Sequencing in Patients with Breast Cancer Having Germline BRCA1/2 Mutation. | Kim JW | Cancer research and treatment | 2023 | PMID: 35681111 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays. | Bouwman P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2020 | PMID: 32546644 |
| Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". | Dines JN | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31911673 |
| Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help? | Zuntini R | Frontiers in genetics | 2018 | PMID: 30254663 |
| A Bayesian framework for efficient and accurate variant prediction. | Qian D | PloS one | 2018 | PMID: 30212499 |
| Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar. | Harrison SM | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28301460 |
| Eligibility Criteria and Genetic Testing Results from a High-Risk Cohort for Hereditary Breast and Ovarian Cancer Syndrome in Southeastern Ontario. | Dos Santos Vidal R | The Journal of molecular diagnostics : JMD | 2016 | PMID: 26941049 |
Text-mined citations for rs199540030 ...
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
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Record last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.