The c.1233T>G variant in BRCA1 is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 411 (p.Asp411Glu). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.0002413 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.07, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP1_Strong, BS3).
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.1233T>G (p.Asp411Glu)
Germline
Reviewed by expert panel
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Reviewed by expert panel. Learn more about how ClinVar calculates review status.
Benign
for
BRCA1-related cancer predisposition
Classification is based on the expert panel submission
Jun 2024 by
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Pane…
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FDA Recognized Database
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.1233T>G (p.Asp411Glu)
Variation ID: 41804 Accession: VCV000041804.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43094298 (GRCh38) [ NCBI UCSC ] 17: 41246315 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 12, 2013 Jun 8, 2025 Jun 11, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.1233T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Asp411Glu missense NM_001407571.1:c.1020T>G NP_001394500.1:p.Asp340Glu missense NM_001407581.1:c.1233T>G NP_001394510.1:p.Asp411Glu missense NM_001407582.1:c.1233T>G NP_001394511.1:p.Asp411Glu missense NM_001407583.1:c.1233T>G NP_001394512.1:p.Asp411Glu missense NM_001407585.1:c.1233T>G NP_001394514.1:p.Asp411Glu missense NM_001407587.1:c.1230T>G NP_001394516.1:p.Asp410Glu missense NM_001407590.1:c.1230T>G NP_001394519.1:p.Asp410Glu missense NM_001407591.1:c.1230T>G NP_001394520.1:p.Asp410Glu missense NM_001407593.1:c.1233T>G NP_001394522.1:p.Asp411Glu missense NM_001407594.1:c.1233T>G NP_001394523.1:p.Asp411Glu missense NM_001407596.1:c.1233T>G NP_001394525.1:p.Asp411Glu missense NM_001407597.1:c.1233T>G NP_001394526.1:p.Asp411Glu missense NM_001407598.1:c.1233T>G NP_001394527.1:p.Asp411Glu missense NM_001407602.1:c.1233T>G NP_001394531.1:p.Asp411Glu missense NM_001407603.1:c.1233T>G NP_001394532.1:p.Asp411Glu missense NM_001407605.1:c.1233T>G NP_001394534.1:p.Asp411Glu missense NM_001407610.1:c.1230T>G NP_001394539.1:p.Asp410Glu missense NM_001407611.1:c.1230T>G NP_001394540.1:p.Asp410Glu missense NM_001407612.1:c.1230T>G NP_001394541.1:p.Asp410Glu missense NM_001407613.1:c.1230T>G NP_001394542.1:p.Asp410Glu missense NM_001407614.1:c.1230T>G NP_001394543.1:p.Asp410Glu missense NM_001407615.1:c.1230T>G NP_001394544.1:p.Asp410Glu missense NM_001407616.1:c.1233T>G NP_001394545.1:p.Asp411Glu missense NM_001407617.1:c.1233T>G NP_001394546.1:p.Asp411Glu missense NM_001407618.1:c.1233T>G NP_001394547.1:p.Asp411Glu missense NM_001407619.1:c.1233T>G NP_001394548.1:p.Asp411Glu missense NM_001407620.1:c.1233T>G NP_001394549.1:p.Asp411Glu missense NM_001407621.1:c.1233T>G NP_001394550.1:p.Asp411Glu missense NM_001407622.1:c.1233T>G NP_001394551.1:p.Asp411Glu missense NM_001407623.1:c.1233T>G NP_001394552.1:p.Asp411Glu missense NM_001407624.1:c.1233T>G NP_001394553.1:p.Asp411Glu missense NM_001407625.1:c.1233T>G NP_001394554.1:p.Asp411Glu missense NM_001407626.1:c.1233T>G NP_001394555.1:p.Asp411Glu missense NM_001407627.1:c.1230T>G NP_001394556.1:p.Asp410Glu missense NM_001407628.1:c.1230T>G NP_001394557.1:p.Asp410Glu missense NM_001407629.1:c.1230T>G NP_001394558.1:p.Asp410Glu missense NM_001407630.1:c.1230T>G NP_001394559.1:p.Asp410Glu missense NM_001407631.1:c.1230T>G NP_001394560.1:p.Asp410Glu missense NM_001407632.1:c.1230T>G NP_001394561.1:p.Asp410Glu missense NM_001407633.1:c.1230T>G NP_001394562.1:p.Asp410Glu missense NM_001407634.1:c.1230T>G NP_001394563.1:p.Asp410Glu missense NM_001407635.1:c.1230T>G NP_001394564.1:p.Asp410Glu missense NM_001407636.1:c.1230T>G NP_001394565.1:p.Asp410Glu missense NM_001407637.1:c.1230T>G NP_001394566.1:p.Asp410Glu missense NM_001407638.1:c.1230T>G NP_001394567.1:p.Asp410Glu missense NM_001407639.1:c.1233T>G NP_001394568.1:p.Asp411Glu missense NM_001407640.1:c.1233T>G NP_001394569.1:p.Asp411Glu missense NM_001407641.1:c.1233T>G NP_001394570.1:p.Asp411Glu missense NM_001407642.1:c.1233T>G NP_001394571.1:p.Asp411Glu missense NM_001407644.1:c.1230T>G NP_001394573.1:p.Asp410Glu missense NM_001407645.1:c.1230T>G NP_001394574.1:p.Asp410Glu missense NM_001407646.1:c.1224T>G NP_001394575.1:p.Asp408Glu missense NM_001407647.1:c.1224T>G NP_001394576.1:p.Asp408Glu missense NM_001407648.1:c.1110T>G NP_001394577.1:p.Asp370Glu missense NM_001407649.1:c.1107T>G NP_001394578.1:p.Asp369Glu missense NM_001407652.1:c.1233T>G NP_001394581.1:p.Asp411Glu missense NM_001407653.1:c.1155T>G NP_001394582.1:p.Asp385Glu missense NM_001407654.1:c.1155T>G NP_001394583.1:p.Asp385Glu missense NM_001407655.1:c.1155T>G NP_001394584.1:p.Asp385Glu missense NM_001407656.1:c.1155T>G NP_001394585.1:p.Asp385Glu missense NM_001407657.1:c.1155T>G NP_001394586.1:p.Asp385Glu missense NM_001407658.1:c.1155T>G NP_001394587.1:p.Asp385Glu missense NM_001407659.1:c.1152T>G NP_001394588.1:p.Asp384Glu missense NM_001407660.1:c.1152T>G NP_001394589.1:p.Asp384Glu missense NM_001407661.1:c.1152T>G NP_001394590.1:p.Asp384Glu missense NM_001407662.1:c.1152T>G NP_001394591.1:p.Asp384Glu missense NM_001407663.1:c.1155T>G NP_001394592.1:p.Asp385Glu missense NM_001407664.1:c.1110T>G NP_001394593.1:p.Asp370Glu missense NM_001407665.1:c.1110T>G NP_001394594.1:p.Asp370Glu missense NM_001407666.1:c.1110T>G NP_001394595.1:p.Asp370Glu missense NM_001407667.1:c.1110T>G NP_001394596.1:p.Asp370Glu missense NM_001407668.1:c.1110T>G NP_001394597.1:p.Asp370Glu missense NM_001407669.1:c.1110T>G NP_001394598.1:p.Asp370Glu missense NM_001407670.1:c.1107T>G NP_001394599.1:p.Asp369Glu missense NM_001407671.1:c.1107T>G NP_001394600.1:p.Asp369Glu missense NM_001407672.1:c.1107T>G NP_001394601.1:p.Asp369Glu missense NM_001407673.1:c.1107T>G NP_001394602.1:p.Asp369Glu missense NM_001407674.1:c.1110T>G NP_001394603.1:p.Asp370Glu missense NM_001407675.1:c.1110T>G NP_001394604.1:p.Asp370Glu missense NM_001407676.1:c.1110T>G NP_001394605.1:p.Asp370Glu missense NM_001407677.1:c.1110T>G NP_001394606.1:p.Asp370Glu missense NM_001407678.1:c.1110T>G NP_001394607.1:p.Asp370Glu missense NM_001407679.1:c.1110T>G NP_001394608.1:p.Asp370Glu missense NM_001407680.1:c.1110T>G NP_001394609.1:p.Asp370Glu missense NM_001407681.1:c.1110T>G NP_001394610.1:p.Asp370Glu missense NM_001407682.1:c.1110T>G NP_001394611.1:p.Asp370Glu missense NM_001407683.1:c.1110T>G NP_001394612.1:p.Asp370Glu missense NM_001407684.1:c.1233T>G NP_001394613.1:p.Asp411Glu missense NM_001407685.1:c.1107T>G NP_001394614.1:p.Asp369Glu missense NM_001407686.1:c.1107T>G NP_001394615.1:p.Asp369Glu missense NM_001407687.1:c.1107T>G NP_001394616.1:p.Asp369Glu missense NM_001407688.1:c.1107T>G NP_001394617.1:p.Asp369Glu missense NM_001407689.1:c.1107T>G NP_001394618.1:p.Asp369Glu missense NM_001407690.1:c.1107T>G NP_001394619.1:p.Asp369Glu missense NM_001407691.1:c.1107T>G NP_001394620.1:p.Asp369Glu missense NM_001407692.1:c.1092T>G NP_001394621.1:p.Asp364Glu missense NM_001407694.1:c.1092T>G NP_001394623.1:p.Asp364Glu missense NM_001407695.1:c.1092T>G NP_001394624.1:p.Asp364Glu missense NM_001407696.1:c.1092T>G NP_001394625.1:p.Asp364Glu missense NM_001407697.1:c.1092T>G NP_001394626.1:p.Asp364Glu missense NM_001407698.1:c.1092T>G NP_001394627.1:p.Asp364Glu missense NM_001407724.1:c.1092T>G NP_001394653.1:p.Asp364Glu missense NM_001407725.1:c.1092T>G NP_001394654.1:p.Asp364Glu missense NM_001407726.1:c.1092T>G NP_001394655.1:p.Asp364Glu missense NM_001407727.1:c.1092T>G NP_001394656.1:p.Asp364Glu missense NM_001407728.1:c.1092T>G NP_001394657.1:p.Asp364Glu missense NM_001407729.1:c.1092T>G NP_001394658.1:p.Asp364Glu missense NM_001407730.1:c.1092T>G NP_001394659.1:p.Asp364Glu missense NM_001407731.1:c.1092T>G NP_001394660.1:p.Asp364Glu missense NM_001407732.1:c.1092T>G NP_001394661.1:p.Asp364Glu missense NM_001407733.1:c.1092T>G NP_001394662.1:p.Asp364Glu missense NM_001407734.1:c.1092T>G NP_001394663.1:p.Asp364Glu missense NM_001407735.1:c.1092T>G NP_001394664.1:p.Asp364Glu missense NM_001407736.1:c.1092T>G NP_001394665.1:p.Asp364Glu missense NM_001407737.1:c.1092T>G NP_001394666.1:p.Asp364Glu missense NM_001407738.1:c.1092T>G NP_001394667.1:p.Asp364Glu missense NM_001407739.1:c.1092T>G NP_001394668.1:p.Asp364Glu missense NM_001407740.1:c.1089T>G NP_001394669.1:p.Asp363Glu missense NM_001407741.1:c.1089T>G NP_001394670.1:p.Asp363Glu missense NM_001407742.1:c.1089T>G NP_001394671.1:p.Asp363Glu missense NM_001407743.1:c.1089T>G NP_001394672.1:p.Asp363Glu missense NM_001407744.1:c.1089T>G NP_001394673.1:p.Asp363Glu missense NM_001407745.1:c.1089T>G NP_001394674.1:p.Asp363Glu missense NM_001407746.1:c.1089T>G NP_001394675.1:p.Asp363Glu missense NM_001407747.1:c.1089T>G NP_001394676.1:p.Asp363Glu missense NM_001407748.1:c.1089T>G NP_001394677.1:p.Asp363Glu missense NM_001407749.1:c.1089T>G NP_001394678.1:p.Asp363Glu missense NM_001407750.1:c.1092T>G NP_001394679.1:p.Asp364Glu missense NM_001407751.1:c.1092T>G NP_001394680.1:p.Asp364Glu missense NM_001407752.1:c.1092T>G NP_001394681.1:p.Asp364Glu missense NM_001407838.1:c.1089T>G NP_001394767.1:p.Asp363Glu missense NM_001407839.1:c.1089T>G NP_001394768.1:p.Asp363Glu missense NM_001407841.1:c.1089T>G NP_001394770.1:p.Asp363Glu missense NM_001407842.1:c.1089T>G NP_001394771.1:p.Asp363Glu missense NM_001407843.1:c.1089T>G NP_001394772.1:p.Asp363Glu missense NM_001407844.1:c.1089T>G NP_001394773.1:p.Asp363Glu missense NM_001407845.1:c.1089T>G NP_001394774.1:p.Asp363Glu missense NM_001407846.1:c.1089T>G NP_001394775.1:p.Asp363Glu missense NM_001407847.1:c.1089T>G NP_001394776.1:p.Asp363Glu missense NM_001407848.1:c.1089T>G NP_001394777.1:p.Asp363Glu missense NM_001407849.1:c.1089T>G NP_001394778.1:p.Asp363Glu missense NM_001407850.1:c.1092T>G NP_001394779.1:p.Asp364Glu missense NM_001407851.1:c.1092T>G NP_001394780.1:p.Asp364Glu missense NM_001407852.1:c.1092T>G NP_001394781.1:p.Asp364Glu missense NM_001407853.1:c.1020T>G NP_001394782.1:p.Asp340Glu missense NM_001407854.1:c.1233T>G NP_001394783.1:p.Asp411Glu missense NM_001407858.1:c.1233T>G NP_001394787.1:p.Asp411Glu missense NM_001407859.1:c.1233T>G NP_001394788.1:p.Asp411Glu missense NM_001407860.1:c.1230T>G NP_001394789.1:p.Asp410Glu missense NM_001407861.1:c.1230T>G NP_001394790.1:p.Asp410Glu missense NM_001407862.1:c.1032T>G NP_001394791.1:p.Asp344Glu missense NM_001407863.1:c.1110T>G NP_001394792.1:p.Asp370Glu missense NM_001407874.1:c.1029T>G NP_001394803.1:p.Asp343Glu missense NM_001407875.1:c.1029T>G NP_001394804.1:p.Asp343Glu missense NM_001407879.1:c.1023T>G NP_001394808.1:p.Asp341Glu missense NM_001407881.1:c.1023T>G NP_001394810.1:p.Asp341Glu missense NM_001407882.1:c.1023T>G NP_001394811.1:p.Asp341Glu missense NM_001407884.1:c.1023T>G NP_001394813.1:p.Asp341Glu missense NM_001407885.1:c.1023T>G NP_001394814.1:p.Asp341Glu missense NM_001407886.1:c.1023T>G NP_001394815.1:p.Asp341Glu missense NM_001407887.1:c.1023T>G NP_001394816.1:p.Asp341Glu missense NM_001407889.1:c.1023T>G NP_001394818.1:p.Asp341Glu missense NM_001407894.1:c.1020T>G NP_001394823.1:p.Asp340Glu missense NM_001407895.1:c.1020T>G NP_001394824.1:p.Asp340Glu missense NM_001407896.1:c.1020T>G NP_001394825.1:p.Asp340Glu missense NM_001407897.1:c.1020T>G NP_001394826.1:p.Asp340Glu missense NM_001407898.1:c.1020T>G NP_001394827.1:p.Asp340Glu missense NM_001407899.1:c.1020T>G NP_001394828.1:p.Asp340Glu missense NM_001407900.1:c.1023T>G NP_001394829.1:p.Asp341Glu missense NM_001407902.1:c.1023T>G NP_001394831.1:p.Asp341Glu missense NM_001407904.1:c.1023T>G NP_001394833.1:p.Asp341Glu missense NM_001407906.1:c.1023T>G NP_001394835.1:p.Asp341Glu missense NM_001407907.1:c.1023T>G NP_001394836.1:p.Asp341Glu missense NM_001407908.1:c.1023T>G NP_001394837.1:p.Asp341Glu missense NM_001407909.1:c.1023T>G NP_001394838.1:p.Asp341Glu missense NM_001407910.1:c.1023T>G NP_001394839.1:p.Asp341Glu missense NM_001407915.1:c.1020T>G NP_001394844.1:p.Asp340Glu missense NM_001407916.1:c.1020T>G NP_001394845.1:p.Asp340Glu missense NM_001407917.1:c.1020T>G NP_001394846.1:p.Asp340Glu missense NM_001407918.1:c.1020T>G NP_001394847.1:p.Asp340Glu missense NM_001407919.1:c.1110T>G NP_001394848.1:p.Asp370Glu missense NM_001407920.1:c.969T>G NP_001394849.1:p.Asp323Glu missense NM_001407921.1:c.969T>G NP_001394850.1:p.Asp323Glu missense NM_001407922.1:c.969T>G NP_001394851.1:p.Asp323Glu missense NM_001407923.1:c.969T>G NP_001394852.1:p.Asp323Glu missense NM_001407924.1:c.969T>G NP_001394853.1:p.Asp323Glu missense NM_001407925.1:c.969T>G NP_001394854.1:p.Asp323Glu missense NM_001407926.1:c.969T>G NP_001394855.1:p.Asp323Glu missense NM_001407927.1:c.969T>G NP_001394856.1:p.Asp323Glu missense NM_001407928.1:c.969T>G NP_001394857.1:p.Asp323Glu missense NM_001407929.1:c.969T>G NP_001394858.1:p.Asp323Glu missense NM_001407930.1:c.966T>G NP_001394859.1:p.Asp322Glu missense NM_001407931.1:c.966T>G NP_001394860.1:p.Asp322Glu missense NM_001407932.1:c.966T>G NP_001394861.1:p.Asp322Glu missense NM_001407933.1:c.969T>G NP_001394862.1:p.Asp323Glu missense NM_001407934.1:c.966T>G NP_001394863.1:p.Asp322Glu missense NM_001407935.1:c.969T>G NP_001394864.1:p.Asp323Glu missense NM_001407936.1:c.966T>G NP_001394865.1:p.Asp322Glu missense NM_001407937.1:c.1110T>G NP_001394866.1:p.Asp370Glu missense NM_001407938.1:c.1110T>G NP_001394867.1:p.Asp370Glu missense NM_001407939.1:c.1110T>G NP_001394868.1:p.Asp370Glu missense NM_001407940.1:c.1107T>G NP_001394869.1:p.Asp369Glu missense NM_001407941.1:c.1107T>G NP_001394870.1:p.Asp369Glu missense NM_001407942.1:c.1092T>G NP_001394871.1:p.Asp364Glu missense NM_001407943.1:c.1089T>G NP_001394872.1:p.Asp363Glu missense NM_001407944.1:c.1092T>G NP_001394873.1:p.Asp364Glu missense NM_001407945.1:c.1092T>G NP_001394874.1:p.Asp364Glu missense NM_001407946.1:c.900T>G NP_001394875.1:p.Asp300Glu missense NM_001407947.1:c.900T>G NP_001394876.1:p.Asp300Glu missense NM_001407948.1:c.900T>G NP_001394877.1:p.Asp300Glu missense NM_001407949.1:c.900T>G NP_001394878.1:p.Asp300Glu missense NM_001407950.1:c.900T>G NP_001394879.1:p.Asp300Glu missense NM_001407951.1:c.900T>G NP_001394880.1:p.Asp300Glu missense NM_001407952.1:c.900T>G NP_001394881.1:p.Asp300Glu missense NM_001407953.1:c.900T>G NP_001394882.1:p.Asp300Glu missense NM_001407954.1:c.897T>G NP_001394883.1:p.Asp299Glu missense NM_001407955.1:c.897T>G NP_001394884.1:p.Asp299Glu missense NM_001407956.1:c.897T>G NP_001394885.1:p.Asp299Glu missense NM_001407957.1:c.900T>G NP_001394886.1:p.Asp300Glu missense NM_001407958.1:c.897T>G NP_001394887.1:p.Asp299Glu missense NM_001407959.1:c.852T>G NP_001394888.1:p.Asp284Glu missense NM_001407960.1:c.852T>G NP_001394889.1:p.Asp284Glu missense NM_001407962.1:c.849T>G NP_001394891.1:p.Asp283Glu missense NM_001407963.1:c.852T>G NP_001394892.1:p.Asp284Glu missense NM_001407964.1:c.1089T>G NP_001394893.1:p.Asp363Glu missense NM_001407965.1:c.729T>G NP_001394894.1:p.Asp243Glu missense NM_001407966.1:c.345T>G NP_001394895.1:p.Asp115Glu missense NM_001407967.1:c.345T>G NP_001394896.1:p.Asp115Glu missense NM_001407968.1:c.787+446T>G intron variant NM_001407969.1:c.787+446T>G intron variant NM_001407970.1:c.787+446T>G intron variant NM_001407971.1:c.787+446T>G intron variant NM_001407972.1:c.784+446T>G intron variant NM_001407973.1:c.787+446T>G intron variant NM_001407974.1:c.787+446T>G intron variant NM_001407975.1:c.787+446T>G intron variant NM_001407976.1:c.787+446T>G intron variant NM_001407977.1:c.787+446T>G intron variant NM_001407978.1:c.787+446T>G intron variant NM_001407979.1:c.787+446T>G intron variant NM_001407980.1:c.787+446T>G intron variant NM_001407981.1:c.787+446T>G intron variant NM_001407982.1:c.787+446T>G intron variant NM_001407983.1:c.787+446T>G intron variant NM_001407984.1:c.784+446T>G intron variant NM_001407985.1:c.784+446T>G intron variant NM_001407986.1:c.784+446T>G intron variant NM_001407990.1:c.787+446T>G intron variant NM_001407991.1:c.784+446T>G intron variant NM_001407992.1:c.784+446T>G intron variant NM_001407993.1:c.787+446T>G intron variant NM_001408392.1:c.784+446T>G intron variant NM_001408396.1:c.784+446T>G intron variant NM_001408397.1:c.784+446T>G intron variant NM_001408398.1:c.784+446T>G intron variant NM_001408399.1:c.784+446T>G intron variant NM_001408400.1:c.784+446T>G intron variant NM_001408401.1:c.784+446T>G intron variant NM_001408402.1:c.784+446T>G intron variant NM_001408403.1:c.787+446T>G intron variant NM_001408404.1:c.787+446T>G intron variant NM_001408406.1:c.790+443T>G intron variant NM_001408407.1:c.784+446T>G intron variant NM_001408408.1:c.778+446T>G intron variant NM_001408409.1:c.709+446T>G intron variant NM_001408410.1:c.646+446T>G intron variant NM_001408411.1:c.709+446T>G intron variant NM_001408412.1:c.709+446T>G intron variant NM_001408413.1:c.706+446T>G intron variant NM_001408414.1:c.709+446T>G intron variant NM_001408415.1:c.709+446T>G intron variant NM_001408416.1:c.706+446T>G intron variant NM_001408418.1:c.670+1548T>G intron variant NM_001408419.1:c.670+1548T>G intron variant NM_001408420.1:c.670+1548T>G intron variant NM_001408421.1:c.667+1548T>G intron variant NM_001408422.1:c.670+1548T>G intron variant NM_001408423.1:c.670+1548T>G intron variant NM_001408424.1:c.667+1548T>G intron variant NM_001408425.1:c.664+446T>G intron variant NM_001408426.1:c.664+446T>G intron variant NM_001408427.1:c.664+446T>G intron variant NM_001408428.1:c.664+446T>G intron variant NM_001408429.1:c.664+446T>G intron variant NM_001408430.1:c.664+446T>G intron variant NM_001408431.1:c.667+1548T>G intron variant NM_001408432.1:c.661+446T>G intron variant NM_001408433.1:c.661+446T>G intron variant NM_001408434.1:c.661+446T>G intron variant NM_001408435.1:c.661+446T>G intron variant NM_001408436.1:c.664+446T>G intron variant NM_001408437.1:c.664+446T>G intron variant NM_001408438.1:c.664+446T>G intron variant NM_001408439.1:c.664+446T>G intron variant NM_001408440.1:c.664+446T>G intron variant NM_001408441.1:c.664+446T>G intron variant NM_001408442.1:c.664+446T>G intron variant NM_001408443.1:c.664+446T>G intron variant NM_001408444.1:c.664+446T>G intron variant NM_001408445.1:c.661+446T>G intron variant NM_001408446.1:c.661+446T>G intron variant NM_001408447.1:c.661+446T>G intron variant NM_001408448.1:c.661+446T>G intron variant NM_001408450.1:c.661+446T>G intron variant NM_001408451.1:c.652+446T>G intron variant NM_001408452.1:c.646+446T>G intron variant NM_001408453.1:c.646+446T>G intron variant NM_001408454.1:c.646+446T>G intron variant NM_001408455.1:c.646+446T>G intron variant NM_001408456.1:c.646+446T>G intron variant NM_001408457.1:c.646+446T>G intron variant NM_001408458.1:c.646+446T>G intron variant NM_001408459.1:c.646+446T>G intron variant NM_001408460.1:c.646+446T>G intron variant NM_001408461.1:c.646+446T>G intron variant NM_001408462.1:c.643+446T>G intron variant NM_001408463.1:c.643+446T>G intron variant NM_001408464.1:c.643+446T>G intron variant NM_001408465.1:c.643+446T>G intron variant NM_001408466.1:c.646+446T>G intron variant NM_001408467.1:c.646+446T>G intron variant NM_001408468.1:c.643+446T>G intron variant NM_001408469.1:c.646+446T>G intron variant NM_001408470.1:c.643+446T>G intron variant NM_001408472.1:c.787+446T>G intron variant NM_001408473.1:c.784+446T>G intron variant NM_001408474.1:c.586+446T>G intron variant NM_001408475.1:c.583+446T>G intron variant NM_001408476.1:c.586+446T>G intron variant NM_001408478.1:c.577+446T>G intron variant NM_001408479.1:c.577+446T>G intron variant NM_001408480.1:c.577+446T>G intron variant NM_001408481.1:c.577+446T>G intron variant NM_001408482.1:c.577+446T>G intron variant NM_001408483.1:c.577+446T>G intron variant NM_001408484.1:c.577+446T>G intron variant NM_001408485.1:c.577+446T>G intron variant NM_001408489.1:c.577+446T>G intron variant NM_001408490.1:c.574+446T>G intron variant NM_001408491.1:c.574+446T>G intron variant NM_001408492.1:c.577+446T>G intron variant NM_001408493.1:c.574+446T>G intron variant NM_001408494.1:c.548-3266T>G intron variant NM_001408495.1:c.545-3266T>G intron variant NM_001408496.1:c.523+446T>G intron variant NM_001408497.1:c.523+446T>G intron variant NM_001408498.1:c.523+446T>G intron variant NM_001408499.1:c.523+446T>G intron variant NM_001408500.1:c.523+446T>G intron variant NM_001408501.1:c.523+446T>G intron variant NM_001408502.1:c.454+446T>G intron variant NM_001408503.1:c.520+446T>G intron variant NM_001408504.1:c.520+446T>G intron variant NM_001408505.1:c.520+446T>G intron variant NM_001408506.1:c.460+1548T>G intron variant NM_001408507.1:c.460+1548T>G intron variant NM_001408508.1:c.451+446T>G intron variant NM_001408509.1:c.451+446T>G intron variant NM_001408510.1:c.406+446T>G intron variant NM_001408511.1:c.404-3266T>G intron variant NM_001408512.1:c.283+446T>G intron variant NM_001408513.1:c.577+446T>G intron variant NM_001408514.1:c.577+446T>G intron variant NM_007297.4:c.1092T>G NP_009228.2:p.Asp364Glu missense NM_007298.4:c.787+446T>G intron variant NM_007299.4:c.787+446T>G intron variant NM_007300.4:c.1233T>G NP_009231.2:p.Asp411Glu missense NR_027676.1:n.1369T>G NC_000017.11:g.43094298A>C NC_000017.10:g.41246315A>C NG_005905.2:g.123686T>G LRG_292:g.123686T>G LRG_292t1:c.1233T>G LRG_292p1:p.Asp411Glu U14680.1:n.1352T>G - Protein change
- D411E, D364E, D300E, D323E, D344E, D410E, D283E, D322E, D340E, D384E, D385E, D408E, D115E, D243E, D284E, D299E, D370E, D341E, D343E, D363E, D369E
- Other names
-
NM_007294.4(BRCA1):c.1233T>G
1352T>G
- Canonical SPDI
- NC_000017.11:43094297:A: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.
-
0.00020 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00013
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00017
- 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 |
13536 | 15443 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 18, 2024 | RCV000034726.10 | |
| Benign (3) |
reviewed by expert panel
|
Feb 5, 2024 | RCV000083166.11 | |
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 17, 2024 | RCV000130781.11 | |
| Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 27, 2024 | RCV000428573.9 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 20, 2025 | RCV001080838.8 | |
| Benign (1) |
reviewed by expert panel
|
Jun 11, 2024 | RCV004566801.1 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001356304.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Benign
(Jun 11, 2024)
C
Contributing to aggregate classification
|
reviewed by expert panel
Method: curation
|
BRCA1-related cancer predisposition
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV004101451.2 First in ClinVar: Nov 11, 2023 Last updated: Jun 17, 2024 |
Comment:
The c.1233T>G variant in BRCA1 is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 411 (p.Asp411Glu). The … (more)
The c.1233T>G variant in BRCA1 is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 411 (p.Asp411Glu). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.0002413 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.07, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP1_Strong, BS3). (less)
|
|
|
Benign
(Apr 18, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV005878957.1
First in ClinVar: Mar 11, 2025 Last updated: Mar 11, 2025 |
|
|
|
Likely benign
(Nov 21, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000517031.4
First in ClinVar: Mar 08, 2017 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
|
|
Likely benign
(Dec 05, 2019)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600244.3
First in ClinVar: Mar 08, 2017 Last updated: Jan 26, 2021 |
|
|
|
Benign
(Feb 05, 2024)
N
Not contributing to aggregate classification
|
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: SCV004818359.1
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: 9
Zygosity: Single Heterozygote
|
|
|
Likely benign
(Dec 10, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185674.7
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)
|
|
|
Likely benign
(Nov 27, 2024)
N
Not contributing to aggregate classification
|
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: SCV000698836.6
First in ClinVar: Apr 12, 2013 Last updated: Feb 16, 2025 |
Comment:
Variant summary: BRCA1 c.1233T>G (p.Asp411Glu) results in a conservative amino acid change located in the serine-rich domain (IPR025994) of the encoded protein sequence. Five of … (more)
Variant summary: BRCA1 c.1233T>G (p.Asp411Glu) results in a conservative amino acid change located in the 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 2.9e-05 in 349536 control chromosomes, predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database. Though this frequency is not higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00049 vs 0.001), the variant might still represent a benign polymorphism. In addition, the variant was also reported in 1/7325 European American women (frequency: 0.00014) and 2/2559 African American women (frequency: 0.0008), who were older than age 70 years and have never had cancer (in the FLOSSIES database). Overall, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1233T>G has been reported in the literature as a VUS in settings of multigene panel testing/custom genotyping arrays in cohorts of individuals with breast cancer (example, Maxwell_2014, Judkins_2005, Abkevich_2004, Shimelis_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15235020, 16518693, 22703879, 16267036, 25503501, 21523855, 15385441, 28283652). ClinVar contains an entry for this variant (Variation ID: 41804). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Likely benign
(Jan 20, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000075400.13
First in ClinVar: Jul 03, 2013 Last updated: Feb 25, 2025 |
|
|
|
Benign
(Sep 17, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000903235.2
First in ClinVar: May 20, 2019 Last updated: May 03, 2025 |
Platform type: NGS
|
|
|
Likely benign
(Dec 07, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002538005.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Uncertain significance
(May 29, 2002)
N
Not contributing to aggregate classification
|
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: SCV000144035.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 2
Ethnicity/Population group: African
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: African American
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Native American
|
|
|
Benign
(May 01, 2012)
N
Not contributing to aggregate classification
|
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: SCV000115240.3
First in ClinVar: Feb 06, 2014 Last updated: Sep 27, 2014 |
|
|
|
Uncertain significance
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551433.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRCA1 p.Asp411Glu variant was identified in 1 of 556 proband chromosomes (frequency: 0.001798) from individuals or families with early onset breast cancer (Maxwell_2014), and … (more)
The BRCA1 p.Asp411Glu variant was identified in 1 of 556 proband chromosomes (frequency: 0.001798) from individuals or families with early onset breast cancer (Maxwell_2014), and was found in 1 of 1144 chromosomes in an exome sequencing study of a control population of individuals with atherosclerosis (Johnston_2012). The variant was also identified in dbSNP (ID: rs80357024) as “With other allele”, ClinVar (as benign by SCRP, likely benign by Invitae, Ambry Genetics, and GeneDx, and uncertain significance by Quest Diagnostics, BIC and Biesecker Lab), Clinvitae (5x), LOVD 3.0 (3x), UMD-LSDB (4x), and BIC Database (4x) databases. The variant was not identified in COGR, Cosmic, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 276576 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 10 of 24008 chromosomes (freq: 0.000417), Latino in 1 of 34402 chromosomes (freq: 0.000029), and not in the Other, European (Non-Finnish), Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. There are conflicting interpretations in the literature for this variant. Studies based on amino acid conservation classify the variant as neutral (Abkevich_2004, Burk-Herrick_2005), while a study of splicing effects (Mucaki_2010) and a study of early onset breast cancer patients (Maxwell_2014) both classified the variant as unknown significance. The p.Asp411 residue is not conserved in mammals and the variant amino acid Glutamine (Glu) is present in Red junglefowl, increasing the likelihood that this variant does not have clinical significance. 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site. However, HumanSpliceFinder, MaxEntScan, and GeneSplicer predict an altered 5' splice site in this region and Human Splicing Finder predicts an altered 3’ splice site; therefore we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site. 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)
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Uncertain significance
(Jul 13, 2012)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: research
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not provided
Affected status: no
Allele origin:
germline
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043182.2 First in ClinVar: Apr 12, 2013 Last updated: Jun 08, 2025
Comment:
The accession SCV000043182.1 was assigned erroneously to two variants. SCV000043182.1 represents NM_007294.3:c.1233T>G ; NM_001048171.1:c.53C>T is now represented by SCV000043382.1.
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Comment:
Converted during submission from variant of unknown significance to Uncertain significance.
Number of individuals with the variant: 1
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
Platform type: High-Throughput DNA Sequencing
Platform name: Illumina GAIIx
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Comment:
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
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:
Variant summary: BRCA1 c.1233T>G (p.Asp411Glu) results in a conservative amino acid change located in the 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 2.9e-05 in 349536 control chromosomes, predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database. Though this frequency is not higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00049 vs 0.001), the variant might still represent a benign polymorphism. In addition, the variant was also reported in 1/7325 European American women (frequency: 0.00014) and 2/2559 African American women (frequency: 0.0008), who were older than age 70 years and have never had cancer (in the FLOSSIES database). Overall, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1233T>G has been reported in the literature as a VUS in settings of multigene panel testing/custom genotyping arrays in cohorts of individuals with breast cancer (example, Maxwell_2014, Judkins_2005, Abkevich_2004, Shimelis_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15235020, 16518693, 22703879, 16267036, 25503501, 21523855, 15385441, 28283652). ClinVar contains an entry for this variant (Variation ID: 41804). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
The BRCA1 p.Asp411Glu variant was identified in 1 of 556 proband chromosomes (frequency: 0.001798) from individuals or families with early onset breast cancer (Maxwell_2014), and was found in 1 of 1144 chromosomes in an exome sequencing study of a control population of individuals with atherosclerosis (Johnston_2012). The variant was also identified in dbSNP (ID: rs80357024) as “With other allele”, ClinVar (as benign by SCRP, likely benign by Invitae, Ambry Genetics, and GeneDx, and uncertain significance by Quest Diagnostics, BIC and Biesecker Lab), Clinvitae (5x), LOVD 3.0 (3x), UMD-LSDB (4x), and BIC Database (4x) databases. The variant was not identified in COGR, Cosmic, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 276576 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 10 of 24008 chromosomes (freq: 0.000417), Latino in 1 of 34402 chromosomes (freq: 0.000029), and not in the Other, European (Non-Finnish), Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. There are conflicting interpretations in the literature for this variant. Studies based on amino acid conservation classify the variant as neutral (Abkevich_2004, Burk-Herrick_2005), while a study of splicing effects (Mucaki_2010) and a study of early onset breast cancer patients (Maxwell_2014) both classified the variant as unknown significance. The p.Asp411 residue is not conserved in mammals and the variant amino acid Glutamine (Glu) is present in Red junglefowl, increasing the likelihood that this variant does not have clinical significance. 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site. However, HumanSpliceFinder, MaxEntScan, and GeneSplicer predict an altered 5' splice site in this region and Human Splicing Finder predicts an altered 3’ splice site; therefore we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site. 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.
Comment:
Converted during submission from variant of unknown significance to 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:
The c.1233T>G variant in BRCA1 is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 411 (p.Asp411Glu). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.0002413 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.07, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP1_Strong, BS3).
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
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:
Variant summary: BRCA1 c.1233T>G (p.Asp411Glu) results in a conservative amino acid change located in the 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 2.9e-05 in 349536 control chromosomes, predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database. Though this frequency is not higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00049 vs 0.001), the variant might still represent a benign polymorphism. In addition, the variant was also reported in 1/7325 European American women (frequency: 0.00014) and 2/2559 African American women (frequency: 0.0008), who were older than age 70 years and have never had cancer (in the FLOSSIES database). Overall, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1233T>G has been reported in the literature as a VUS in settings of multigene panel testing/custom genotyping arrays in cohorts of individuals with breast cancer (example, Maxwell_2014, Judkins_2005, Abkevich_2004, Shimelis_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15235020, 16518693, 22703879, 16267036, 25503501, 21523855, 15385441, 28283652). ClinVar contains an entry for this variant (Variation ID: 41804). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
The BRCA1 p.Asp411Glu variant was identified in 1 of 556 proband chromosomes (frequency: 0.001798) from individuals or families with early onset breast cancer (Maxwell_2014), and was found in 1 of 1144 chromosomes in an exome sequencing study of a control population of individuals with atherosclerosis (Johnston_2012). The variant was also identified in dbSNP (ID: rs80357024) as “With other allele”, ClinVar (as benign by SCRP, likely benign by Invitae, Ambry Genetics, and GeneDx, and uncertain significance by Quest Diagnostics, BIC and Biesecker Lab), Clinvitae (5x), LOVD 3.0 (3x), UMD-LSDB (4x), and BIC Database (4x) databases. The variant was not identified in COGR, Cosmic, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 276576 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 10 of 24008 chromosomes (freq: 0.000417), Latino in 1 of 34402 chromosomes (freq: 0.000029), and not in the Other, European (Non-Finnish), Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. There are conflicting interpretations in the literature for this variant. Studies based on amino acid conservation classify the variant as neutral (Abkevich_2004, Burk-Herrick_2005), while a study of splicing effects (Mucaki_2010) and a study of early onset breast cancer patients (Maxwell_2014) both classified the variant as unknown significance. The p.Asp411 residue is not conserved in mammals and the variant amino acid Glutamine (Glu) is present in Red junglefowl, increasing the likelihood that this variant does not have clinical significance. 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site. However, HumanSpliceFinder, MaxEntScan, and GeneSplicer predict an altered 5' splice site in this region and Human Splicing Finder predicts an altered 3’ splice site; therefore we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site. 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.
Comment:
Converted during submission from variant of unknown significance to Uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer. | Shimelis H | Cancer research | 2017 | PMID: 28283652 |
| Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. | Maxwell KN | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25503501 |
| Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
| Comprehensive prediction of mRNA splicing effects of BRCA1 and BRCA2 variants. | Mucaki EJ | Human mutation | 2011 | PMID: 21523855 |
| Natural selection and mammalian BRCA1 sequences: elucidating functionally important sites relevant to breast cancer susceptibility in humans. | Burk-Herrick A | Mammalian genome : official journal of the International Mammalian Genome Society | 2006 | PMID: 16518693 |
| Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. | Judkins T | Cancer research | 2005 | PMID: 16267036 |
| Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition. | Pavlicek A | Human molecular genetics | 2004 | PMID: 15385441 |
| Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. | Abkevich V | Journal of medical genetics | 2004 | PMID: 15235020 |
| The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b565abfc-a0e8-4a5b-91dc-fd4ddbc6cc87 | - | - | - | - |
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Text-mined citations for rs80357024 ...
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Record last updated Jun 08, 2025
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.