Variant summary: The BRCA1 c.1427A>G (p.His476Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide located in the BRCA1, serine-rich domain (IPR025994) (InterPro). 3/5 in silico tools predict a damaging outcome for this variant. A functional study showed no dramatic effect on splicing for this variant (Anczukow_Genes Chromosomes and Cancer_2008). This variant was found in 34/121588 control chromosomes in the control population ExAc and in published studies, predominantly observed in the African subpopulation at a frequency of 0.00298 (31/10404). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has been reported in affected individuals via publications including one paper reporting the variant to co-occur with another deleterious BRCA1 variant, c.943ins10 (Judkins_2005) referenced in BIC, which also reports another individual with a co-occurring deleterious BRCA2 variant, c.5616_5620delAGTAA. This variant is found in two internal specimens co-occuring with pathogenic variants BRCA2 c.2957_2958insG and PMS2 c.2186_2187delTC. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.1427A>G (p.His476Arg)
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.
Benign/Likely benign
15
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.1427A>G (p.His476Arg)
Variation ID: 54251 Accession: VCV000054251.41
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.31 17: 43094104 (GRCh38) [ NCBI UCSC ] 17: 41246121 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 1, 2014 May 1, 2024 Feb 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.1427A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.His476Arg missense NM_001407571.1:c.1214A>G NP_001394500.1:p.His405Arg missense NM_001407581.1:c.1427A>G NP_001394510.1:p.His476Arg missense NM_001407582.1:c.1427A>G NP_001394511.1:p.His476Arg missense NM_001407583.1:c.1427A>G NP_001394512.1:p.His476Arg missense NM_001407585.1:c.1427A>G NP_001394514.1:p.His476Arg missense NM_001407587.1:c.1424A>G NP_001394516.1:p.His475Arg missense NM_001407590.1:c.1424A>G NP_001394519.1:p.His475Arg missense NM_001407591.1:c.1424A>G NP_001394520.1:p.His475Arg missense NM_001407593.1:c.1427A>G NP_001394522.1:p.His476Arg missense NM_001407594.1:c.1427A>G NP_001394523.1:p.His476Arg missense NM_001407596.1:c.1427A>G NP_001394525.1:p.His476Arg missense NM_001407597.1:c.1427A>G NP_001394526.1:p.His476Arg missense NM_001407598.1:c.1427A>G NP_001394527.1:p.His476Arg missense NM_001407602.1:c.1427A>G NP_001394531.1:p.His476Arg missense NM_001407603.1:c.1427A>G NP_001394532.1:p.His476Arg missense NM_001407605.1:c.1427A>G NP_001394534.1:p.His476Arg missense NM_001407610.1:c.1424A>G NP_001394539.1:p.His475Arg missense NM_001407611.1:c.1424A>G NP_001394540.1:p.His475Arg missense NM_001407612.1:c.1424A>G NP_001394541.1:p.His475Arg missense NM_001407613.1:c.1424A>G NP_001394542.1:p.His475Arg missense NM_001407614.1:c.1424A>G NP_001394543.1:p.His475Arg missense NM_001407615.1:c.1424A>G NP_001394544.1:p.His475Arg missense NM_001407616.1:c.1427A>G NP_001394545.1:p.His476Arg missense NM_001407617.1:c.1427A>G NP_001394546.1:p.His476Arg missense NM_001407618.1:c.1427A>G NP_001394547.1:p.His476Arg missense NM_001407619.1:c.1427A>G NP_001394548.1:p.His476Arg missense NM_001407620.1:c.1427A>G NP_001394549.1:p.His476Arg missense NM_001407621.1:c.1427A>G NP_001394550.1:p.His476Arg missense NM_001407622.1:c.1427A>G NP_001394551.1:p.His476Arg missense NM_001407623.1:c.1427A>G NP_001394552.1:p.His476Arg missense NM_001407624.1:c.1427A>G NP_001394553.1:p.His476Arg missense NM_001407625.1:c.1427A>G NP_001394554.1:p.His476Arg missense NM_001407626.1:c.1427A>G NP_001394555.1:p.His476Arg missense NM_001407627.1:c.1424A>G NP_001394556.1:p.His475Arg missense NM_001407628.1:c.1424A>G NP_001394557.1:p.His475Arg missense NM_001407629.1:c.1424A>G NP_001394558.1:p.His475Arg missense NM_001407630.1:c.1424A>G NP_001394559.1:p.His475Arg missense NM_001407631.1:c.1424A>G NP_001394560.1:p.His475Arg missense NM_001407632.1:c.1424A>G NP_001394561.1:p.His475Arg missense NM_001407633.1:c.1424A>G NP_001394562.1:p.His475Arg missense NM_001407634.1:c.1424A>G NP_001394563.1:p.His475Arg missense NM_001407635.1:c.1424A>G NP_001394564.1:p.His475Arg missense NM_001407636.1:c.1424A>G NP_001394565.1:p.His475Arg missense NM_001407637.1:c.1424A>G NP_001394566.1:p.His475Arg missense NM_001407638.1:c.1424A>G NP_001394567.1:p.His475Arg missense NM_001407639.1:c.1427A>G NP_001394568.1:p.His476Arg missense NM_001407640.1:c.1427A>G NP_001394569.1:p.His476Arg missense NM_001407641.1:c.1427A>G NP_001394570.1:p.His476Arg missense NM_001407642.1:c.1427A>G NP_001394571.1:p.His476Arg missense NM_001407644.1:c.1424A>G NP_001394573.1:p.His475Arg missense NM_001407645.1:c.1424A>G NP_001394574.1:p.His475Arg missense NM_001407646.1:c.1418A>G NP_001394575.1:p.His473Arg missense NM_001407647.1:c.1418A>G NP_001394576.1:p.His473Arg missense NM_001407648.1:c.1304A>G NP_001394577.1:p.His435Arg missense NM_001407649.1:c.1301A>G NP_001394578.1:p.His434Arg missense NM_001407652.1:c.1427A>G NP_001394581.1:p.His476Arg missense NM_001407653.1:c.1349A>G NP_001394582.1:p.His450Arg missense NM_001407654.1:c.1349A>G NP_001394583.1:p.His450Arg missense NM_001407655.1:c.1349A>G NP_001394584.1:p.His450Arg missense NM_001407656.1:c.1349A>G NP_001394585.1:p.His450Arg missense NM_001407657.1:c.1349A>G NP_001394586.1:p.His450Arg missense NM_001407658.1:c.1349A>G NP_001394587.1:p.His450Arg missense NM_001407659.1:c.1346A>G NP_001394588.1:p.His449Arg missense NM_001407660.1:c.1346A>G NP_001394589.1:p.His449Arg missense NM_001407661.1:c.1346A>G NP_001394590.1:p.His449Arg missense NM_001407662.1:c.1346A>G NP_001394591.1:p.His449Arg missense NM_001407663.1:c.1349A>G NP_001394592.1:p.His450Arg missense NM_001407664.1:c.1304A>G NP_001394593.1:p.His435Arg missense NM_001407665.1:c.1304A>G NP_001394594.1:p.His435Arg missense NM_001407666.1:c.1304A>G NP_001394595.1:p.His435Arg missense NM_001407667.1:c.1304A>G NP_001394596.1:p.His435Arg missense NM_001407668.1:c.1304A>G NP_001394597.1:p.His435Arg missense NM_001407669.1:c.1304A>G NP_001394598.1:p.His435Arg missense NM_001407670.1:c.1301A>G NP_001394599.1:p.His434Arg missense NM_001407671.1:c.1301A>G NP_001394600.1:p.His434Arg missense NM_001407672.1:c.1301A>G NP_001394601.1:p.His434Arg missense NM_001407673.1:c.1301A>G NP_001394602.1:p.His434Arg missense NM_001407674.1:c.1304A>G NP_001394603.1:p.His435Arg missense NM_001407675.1:c.1304A>G NP_001394604.1:p.His435Arg missense NM_001407676.1:c.1304A>G NP_001394605.1:p.His435Arg missense NM_001407677.1:c.1304A>G NP_001394606.1:p.His435Arg missense NM_001407678.1:c.1304A>G NP_001394607.1:p.His435Arg missense NM_001407679.1:c.1304A>G NP_001394608.1:p.His435Arg missense NM_001407680.1:c.1304A>G NP_001394609.1:p.His435Arg missense NM_001407681.1:c.1304A>G NP_001394610.1:p.His435Arg missense NM_001407682.1:c.1304A>G NP_001394611.1:p.His435Arg missense NM_001407683.1:c.1304A>G NP_001394612.1:p.His435Arg missense NM_001407684.1:c.1427A>G NP_001394613.1:p.His476Arg missense NM_001407685.1:c.1301A>G NP_001394614.1:p.His434Arg missense NM_001407686.1:c.1301A>G NP_001394615.1:p.His434Arg missense NM_001407687.1:c.1301A>G NP_001394616.1:p.His434Arg missense NM_001407688.1:c.1301A>G NP_001394617.1:p.His434Arg missense NM_001407689.1:c.1301A>G NP_001394618.1:p.His434Arg missense NM_001407690.1:c.1301A>G NP_001394619.1:p.His434Arg missense NM_001407691.1:c.1301A>G NP_001394620.1:p.His434Arg missense NM_001407692.1:c.1286A>G NP_001394621.1:p.His429Arg missense NM_001407694.1:c.1286A>G NP_001394623.1:p.His429Arg missense NM_001407695.1:c.1286A>G NP_001394624.1:p.His429Arg missense NM_001407696.1:c.1286A>G NP_001394625.1:p.His429Arg missense NM_001407697.1:c.1286A>G NP_001394626.1:p.His429Arg missense NM_001407698.1:c.1286A>G NP_001394627.1:p.His429Arg missense NM_001407724.1:c.1286A>G NP_001394653.1:p.His429Arg missense NM_001407725.1:c.1286A>G NP_001394654.1:p.His429Arg missense NM_001407726.1:c.1286A>G NP_001394655.1:p.His429Arg missense NM_001407727.1:c.1286A>G NP_001394656.1:p.His429Arg missense NM_001407728.1:c.1286A>G NP_001394657.1:p.His429Arg missense NM_001407729.1:c.1286A>G NP_001394658.1:p.His429Arg missense NM_001407730.1:c.1286A>G NP_001394659.1:p.His429Arg missense NM_001407731.1:c.1286A>G NP_001394660.1:p.His429Arg missense NM_001407732.1:c.1286A>G NP_001394661.1:p.His429Arg missense NM_001407733.1:c.1286A>G NP_001394662.1:p.His429Arg missense NM_001407734.1:c.1286A>G NP_001394663.1:p.His429Arg missense NM_001407735.1:c.1286A>G NP_001394664.1:p.His429Arg missense NM_001407736.1:c.1286A>G NP_001394665.1:p.His429Arg missense NM_001407737.1:c.1286A>G NP_001394666.1:p.His429Arg missense NM_001407738.1:c.1286A>G NP_001394667.1:p.His429Arg missense NM_001407739.1:c.1286A>G NP_001394668.1:p.His429Arg missense NM_001407740.1:c.1283A>G NP_001394669.1:p.His428Arg missense NM_001407741.1:c.1283A>G NP_001394670.1:p.His428Arg missense NM_001407742.1:c.1283A>G NP_001394671.1:p.His428Arg missense NM_001407743.1:c.1283A>G NP_001394672.1:p.His428Arg missense NM_001407744.1:c.1283A>G NP_001394673.1:p.His428Arg missense NM_001407745.1:c.1283A>G NP_001394674.1:p.His428Arg missense NM_001407746.1:c.1283A>G NP_001394675.1:p.His428Arg missense NM_001407747.1:c.1283A>G NP_001394676.1:p.His428Arg missense NM_001407748.1:c.1283A>G NP_001394677.1:p.His428Arg missense NM_001407749.1:c.1283A>G NP_001394678.1:p.His428Arg missense NM_001407750.1:c.1286A>G NP_001394679.1:p.His429Arg missense NM_001407751.1:c.1286A>G NP_001394680.1:p.His429Arg missense NM_001407752.1:c.1286A>G NP_001394681.1:p.His429Arg missense NM_001407838.1:c.1283A>G NP_001394767.1:p.His428Arg missense NM_001407839.1:c.1283A>G NP_001394768.1:p.His428Arg missense NM_001407841.1:c.1283A>G NP_001394770.1:p.His428Arg missense NM_001407842.1:c.1283A>G NP_001394771.1:p.His428Arg missense NM_001407843.1:c.1283A>G NP_001394772.1:p.His428Arg missense NM_001407844.1:c.1283A>G NP_001394773.1:p.His428Arg missense NM_001407845.1:c.1283A>G NP_001394774.1:p.His428Arg missense NM_001407846.1:c.1283A>G NP_001394775.1:p.His428Arg missense NM_001407847.1:c.1283A>G NP_001394776.1:p.His428Arg missense NM_001407848.1:c.1283A>G NP_001394777.1:p.His428Arg missense NM_001407849.1:c.1283A>G NP_001394778.1:p.His428Arg missense NM_001407850.1:c.1286A>G NP_001394779.1:p.His429Arg missense NM_001407851.1:c.1286A>G NP_001394780.1:p.His429Arg missense NM_001407852.1:c.1286A>G NP_001394781.1:p.His429Arg missense NM_001407853.1:c.1214A>G NP_001394782.1:p.His405Arg missense NM_001407854.1:c.1427A>G NP_001394783.1:p.His476Arg missense NM_001407858.1:c.1427A>G NP_001394787.1:p.His476Arg missense NM_001407859.1:c.1427A>G NP_001394788.1:p.His476Arg missense NM_001407860.1:c.1424A>G NP_001394789.1:p.His475Arg missense NM_001407861.1:c.1424A>G NP_001394790.1:p.His475Arg missense NM_001407862.1:c.1226A>G NP_001394791.1:p.His409Arg missense NM_001407863.1:c.1304A>G NP_001394792.1:p.His435Arg missense NM_001407874.1:c.1223A>G NP_001394803.1:p.His408Arg missense NM_001407875.1:c.1223A>G NP_001394804.1:p.His408Arg missense NM_001407879.1:c.1217A>G NP_001394808.1:p.His406Arg missense NM_001407881.1:c.1217A>G NP_001394810.1:p.His406Arg missense NM_001407882.1:c.1217A>G NP_001394811.1:p.His406Arg missense NM_001407884.1:c.1217A>G NP_001394813.1:p.His406Arg missense NM_001407885.1:c.1217A>G NP_001394814.1:p.His406Arg missense NM_001407886.1:c.1217A>G NP_001394815.1:p.His406Arg missense NM_001407887.1:c.1217A>G NP_001394816.1:p.His406Arg missense NM_001407889.1:c.1217A>G NP_001394818.1:p.His406Arg missense NM_001407894.1:c.1214A>G NP_001394823.1:p.His405Arg missense NM_001407895.1:c.1214A>G NP_001394824.1:p.His405Arg missense NM_001407896.1:c.1214A>G NP_001394825.1:p.His405Arg missense NM_001407897.1:c.1214A>G NP_001394826.1:p.His405Arg missense NM_001407898.1:c.1214A>G NP_001394827.1:p.His405Arg missense NM_001407899.1:c.1214A>G NP_001394828.1:p.His405Arg missense NM_001407900.1:c.1217A>G NP_001394829.1:p.His406Arg missense NM_001407902.1:c.1217A>G NP_001394831.1:p.His406Arg missense NM_001407904.1:c.1217A>G NP_001394833.1:p.His406Arg missense NM_001407906.1:c.1217A>G NP_001394835.1:p.His406Arg missense NM_001407907.1:c.1217A>G NP_001394836.1:p.His406Arg missense NM_001407908.1:c.1217A>G NP_001394837.1:p.His406Arg missense NM_001407909.1:c.1217A>G NP_001394838.1:p.His406Arg missense NM_001407910.1:c.1217A>G NP_001394839.1:p.His406Arg missense NM_001407915.1:c.1214A>G NP_001394844.1:p.His405Arg missense NM_001407916.1:c.1214A>G NP_001394845.1:p.His405Arg missense NM_001407917.1:c.1214A>G NP_001394846.1:p.His405Arg missense NM_001407918.1:c.1214A>G NP_001394847.1:p.His405Arg missense NM_001407919.1:c.1304A>G NP_001394848.1:p.His435Arg missense NM_001407920.1:c.1163A>G NP_001394849.1:p.His388Arg missense NM_001407921.1:c.1163A>G NP_001394850.1:p.His388Arg missense NM_001407922.1:c.1163A>G NP_001394851.1:p.His388Arg missense NM_001407923.1:c.1163A>G NP_001394852.1:p.His388Arg missense NM_001407924.1:c.1163A>G NP_001394853.1:p.His388Arg missense NM_001407925.1:c.1163A>G NP_001394854.1:p.His388Arg missense NM_001407926.1:c.1163A>G NP_001394855.1:p.His388Arg missense NM_001407927.1:c.1163A>G NP_001394856.1:p.His388Arg missense NM_001407928.1:c.1163A>G NP_001394857.1:p.His388Arg missense NM_001407929.1:c.1163A>G NP_001394858.1:p.His388Arg missense NM_001407930.1:c.1160A>G NP_001394859.1:p.His387Arg missense NM_001407931.1:c.1160A>G NP_001394860.1:p.His387Arg missense NM_001407932.1:c.1160A>G NP_001394861.1:p.His387Arg missense NM_001407933.1:c.1163A>G NP_001394862.1:p.His388Arg missense NM_001407934.1:c.1160A>G NP_001394863.1:p.His387Arg missense NM_001407935.1:c.1163A>G NP_001394864.1:p.His388Arg missense NM_001407936.1:c.1160A>G NP_001394865.1:p.His387Arg missense NM_001407937.1:c.1304A>G NP_001394866.1:p.His435Arg missense NM_001407938.1:c.1304A>G NP_001394867.1:p.His435Arg missense NM_001407939.1:c.1304A>G NP_001394868.1:p.His435Arg missense NM_001407940.1:c.1301A>G NP_001394869.1:p.His434Arg missense NM_001407941.1:c.1301A>G NP_001394870.1:p.His434Arg missense NM_001407942.1:c.1286A>G NP_001394871.1:p.His429Arg missense NM_001407943.1:c.1283A>G NP_001394872.1:p.His428Arg missense NM_001407944.1:c.1286A>G NP_001394873.1:p.His429Arg missense NM_001407945.1:c.1286A>G NP_001394874.1:p.His429Arg missense NM_001407946.1:c.1094A>G NP_001394875.1:p.His365Arg missense NM_001407947.1:c.1094A>G NP_001394876.1:p.His365Arg missense NM_001407948.1:c.1094A>G NP_001394877.1:p.His365Arg missense NM_001407949.1:c.1094A>G NP_001394878.1:p.His365Arg missense NM_001407950.1:c.1094A>G NP_001394879.1:p.His365Arg missense NM_001407951.1:c.1094A>G NP_001394880.1:p.His365Arg missense NM_001407952.1:c.1094A>G NP_001394881.1:p.His365Arg missense NM_001407953.1:c.1094A>G NP_001394882.1:p.His365Arg missense NM_001407954.1:c.1091A>G NP_001394883.1:p.His364Arg missense NM_001407955.1:c.1091A>G NP_001394884.1:p.His364Arg missense NM_001407956.1:c.1091A>G NP_001394885.1:p.His364Arg missense NM_001407957.1:c.1094A>G NP_001394886.1:p.His365Arg missense NM_001407958.1:c.1091A>G NP_001394887.1:p.His364Arg missense NM_001407959.1:c.1046A>G NP_001394888.1:p.His349Arg missense NM_001407960.1:c.1046A>G NP_001394889.1:p.His349Arg missense NM_001407962.1:c.1043A>G NP_001394891.1:p.His348Arg missense NM_001407963.1:c.1046A>G NP_001394892.1:p.His349Arg missense NM_001407964.1:c.1283A>G NP_001394893.1:p.His428Arg missense NM_001407965.1:c.923A>G NP_001394894.1:p.His308Arg missense NM_001407966.1:c.539A>G NP_001394895.1:p.His180Arg missense NM_001407967.1:c.539A>G NP_001394896.1:p.His180Arg missense NM_001407968.1:c.787+640A>G intron variant NM_001407969.1:c.787+640A>G intron variant NM_001407970.1:c.787+640A>G intron variant NM_001407971.1:c.787+640A>G intron variant NM_001407972.1:c.784+640A>G intron variant NM_001407973.1:c.787+640A>G intron variant NM_001407974.1:c.787+640A>G intron variant NM_001407975.1:c.787+640A>G intron variant NM_001407976.1:c.787+640A>G intron variant NM_001407977.1:c.787+640A>G intron variant NM_001407978.1:c.787+640A>G intron variant NM_001407979.1:c.787+640A>G intron variant NM_001407980.1:c.787+640A>G intron variant NM_001407981.1:c.787+640A>G intron variant NM_001407982.1:c.787+640A>G intron variant NM_001407983.1:c.787+640A>G intron variant NM_001407984.1:c.784+640A>G intron variant NM_001407985.1:c.784+640A>G intron variant NM_001407986.1:c.784+640A>G intron variant NM_001407990.1:c.787+640A>G intron variant NM_001407991.1:c.784+640A>G intron variant NM_001407992.1:c.784+640A>G intron variant NM_001407993.1:c.787+640A>G intron variant NM_001408392.1:c.784+640A>G intron variant NM_001408396.1:c.784+640A>G intron variant NM_001408397.1:c.784+640A>G intron variant NM_001408398.1:c.784+640A>G intron variant NM_001408399.1:c.784+640A>G intron variant NM_001408400.1:c.784+640A>G intron variant NM_001408401.1:c.784+640A>G intron variant NM_001408402.1:c.784+640A>G intron variant NM_001408403.1:c.787+640A>G intron variant NM_001408404.1:c.787+640A>G intron variant NM_001408406.1:c.790+637A>G intron variant NM_001408407.1:c.784+640A>G intron variant NM_001408408.1:c.778+640A>G intron variant NM_001408409.1:c.709+640A>G intron variant NM_001408410.1:c.646+640A>G intron variant NM_001408411.1:c.709+640A>G intron variant NM_001408412.1:c.709+640A>G intron variant NM_001408413.1:c.706+640A>G intron variant NM_001408414.1:c.709+640A>G intron variant NM_001408415.1:c.709+640A>G intron variant NM_001408416.1:c.706+640A>G intron variant NM_001408418.1:c.670+1742A>G intron variant NM_001408419.1:c.670+1742A>G intron variant NM_001408420.1:c.670+1742A>G intron variant NM_001408421.1:c.667+1742A>G intron variant NM_001408422.1:c.670+1742A>G intron variant NM_001408423.1:c.670+1742A>G intron variant NM_001408424.1:c.667+1742A>G intron variant NM_001408425.1:c.664+640A>G intron variant NM_001408426.1:c.664+640A>G intron variant NM_001408427.1:c.664+640A>G intron variant NM_001408428.1:c.664+640A>G intron variant NM_001408429.1:c.664+640A>G intron variant NM_001408430.1:c.664+640A>G intron variant NM_001408431.1:c.667+1742A>G intron variant NM_001408432.1:c.661+640A>G intron variant NM_001408433.1:c.661+640A>G intron variant NM_001408434.1:c.661+640A>G intron variant NM_001408435.1:c.661+640A>G intron variant NM_001408436.1:c.664+640A>G intron variant NM_001408437.1:c.664+640A>G intron variant NM_001408438.1:c.664+640A>G intron variant NM_001408439.1:c.664+640A>G intron variant NM_001408440.1:c.664+640A>G intron variant NM_001408441.1:c.664+640A>G intron variant NM_001408442.1:c.664+640A>G intron variant NM_001408443.1:c.664+640A>G intron variant NM_001408444.1:c.664+640A>G intron variant NM_001408445.1:c.661+640A>G intron variant NM_001408446.1:c.661+640A>G intron variant NM_001408447.1:c.661+640A>G intron variant NM_001408448.1:c.661+640A>G intron variant NM_001408450.1:c.661+640A>G intron variant NM_001408451.1:c.652+640A>G intron variant NM_001408452.1:c.646+640A>G intron variant NM_001408453.1:c.646+640A>G intron variant NM_001408454.1:c.646+640A>G intron variant NM_001408455.1:c.646+640A>G intron variant NM_001408456.1:c.646+640A>G intron variant NM_001408457.1:c.646+640A>G intron variant NM_001408458.1:c.646+640A>G intron variant NM_001408459.1:c.646+640A>G intron variant NM_001408460.1:c.646+640A>G intron variant NM_001408461.1:c.646+640A>G intron variant NM_001408462.1:c.643+640A>G intron variant NM_001408463.1:c.643+640A>G intron variant NM_001408464.1:c.643+640A>G intron variant NM_001408465.1:c.643+640A>G intron variant NM_001408466.1:c.646+640A>G intron variant NM_001408467.1:c.646+640A>G intron variant NM_001408468.1:c.643+640A>G intron variant NM_001408469.1:c.646+640A>G intron variant NM_001408470.1:c.643+640A>G intron variant NM_001408472.1:c.787+640A>G intron variant NM_001408473.1:c.784+640A>G intron variant NM_001408474.1:c.586+640A>G intron variant NM_001408475.1:c.583+640A>G intron variant NM_001408476.1:c.586+640A>G intron variant NM_001408478.1:c.577+640A>G intron variant NM_001408479.1:c.577+640A>G intron variant NM_001408480.1:c.577+640A>G intron variant NM_001408481.1:c.577+640A>G intron variant NM_001408482.1:c.577+640A>G intron variant NM_001408483.1:c.577+640A>G intron variant NM_001408484.1:c.577+640A>G intron variant NM_001408485.1:c.577+640A>G intron variant NM_001408489.1:c.577+640A>G intron variant NM_001408490.1:c.574+640A>G intron variant NM_001408491.1:c.574+640A>G intron variant NM_001408492.1:c.577+640A>G intron variant NM_001408493.1:c.574+640A>G intron variant NM_001408494.1:c.548-3072A>G intron variant NM_001408495.1:c.545-3072A>G intron variant NM_001408496.1:c.523+640A>G intron variant NM_001408497.1:c.523+640A>G intron variant NM_001408498.1:c.523+640A>G intron variant NM_001408499.1:c.523+640A>G intron variant NM_001408500.1:c.523+640A>G intron variant NM_001408501.1:c.523+640A>G intron variant NM_001408502.1:c.454+640A>G intron variant NM_001408503.1:c.520+640A>G intron variant NM_001408504.1:c.520+640A>G intron variant NM_001408505.1:c.520+640A>G intron variant NM_001408506.1:c.460+1742A>G intron variant NM_001408507.1:c.460+1742A>G intron variant NM_001408508.1:c.451+640A>G intron variant NM_001408509.1:c.451+640A>G intron variant NM_001408510.1:c.406+640A>G intron variant NM_001408511.1:c.404-3072A>G intron variant NM_001408512.1:c.283+640A>G intron variant NM_001408513.1:c.577+640A>G intron variant NM_001408514.1:c.577+640A>G intron variant NM_007297.4:c.1286A>G NP_009228.2:p.His429Arg missense NM_007298.4:c.787+640A>G intron variant NM_007299.4:c.787+640A>G intron variant NM_007300.4:c.1427A>G NP_009231.2:p.His476Arg missense NR_027676.1:n.1563A>G NC_000017.11:g.43094104T>C NC_000017.10:g.41246121T>C NG_005905.2:g.123880A>G LRG_292:g.123880A>G LRG_292t1:c.1427A>G LRG_292p1:p.His476Arg U14680.1:n.1546A>G - Protein change
- H476R, H429R, H364R, H434R, H449R, H180R, H308R, H365R, H388R, H405R, H406R, H428R, H450R, H475R, H349R, H409R, H473R, H348R, H387R, H408R, H435R
- Other names
-
p.H476R:CAT>CGT
NP_009225.1:p.His476Arg
- Canonical SPDI
- NC_000017.11:43094103:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00060 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00018
Exome Aggregation Consortium (ExAC) 0.00028
1000 Genomes Project 0.00060
The Genome Aggregation Database (gnomAD) 0.00066
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
Trans-Omics for Precision Medicine (TOPMed) 0.00079
1000 Genomes Project 30x 0.00094
- 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. |
|---|---|---|---|---|
| Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 5, 2024 | RCV000111616.9 | |
| Likely benign (2) |
criteria provided, single submitter
|
Apr 19, 2021 | RCV000120270.13 | |
| Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 2, 2021 | RCV000130932.10 | |
| Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2022 | RCV000589279.11 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2024 | RCV001082505.8 | |
| Likely benign (1) |
criteria provided, single submitter
|
Nov 11, 2021 | RCV002477163.1 |
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
(Mar 02, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002538027.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
|
|
|
Likely benign
(Mar 10, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000682961.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
|
|
|
Benign
(Jan 24, 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: SCV000075486.15
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
|
|
|
Likely Benign
(Feb 05, 2024)
|
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: SCV004818330.1
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: 42
|
|
|
Benign
(Aug 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698865.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The BRCA1 c.1427A>G (p.His476Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide located in the BRCA1, serine-rich domain (IPR025994) … (more)
Variant summary: The BRCA1 c.1427A>G (p.His476Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide located in the BRCA1, serine-rich domain (IPR025994) (InterPro). 3/5 in silico tools predict a damaging outcome for this variant. A functional study showed no dramatic effect on splicing for this variant (Anczukow_Genes Chromosomes and Cancer_2008). This variant was found in 34/121588 control chromosomes in the control population ExAc and in published studies, predominantly observed in the African subpopulation at a frequency of 0.00298 (31/10404). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has been reported in affected individuals via publications including one paper reporting the variant to co-occur with another deleterious BRCA1 variant, c.943ins10 (Judkins_2005) referenced in BIC, which also reports another individual with a co-occurring deleterious BRCA2 variant, c.5616_5620delAGTAA. This variant is found in two internal specimens co-occuring with pathogenic variants BRCA2 c.2957_2958insG and PMS2 c.2186_2187delTC. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign. (less)
|
|
|
Benign
(Nov 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002026002.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Geographic origin: South Africa
Testing laboratory: National Health Laboratory Service (NHLS)
|
|
|
Likely benign
(Apr 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002070489.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
|
Likely benign
(Dec 30, 2014)
|
criteria provided, single submitter
Method: literature only
|
Breast-ovarian cancer, familial 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220997.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
|
Likely benign
(Nov 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Breast-ovarian cancer, familial, susceptibility to, 1 Pancreatic cancer, susceptibility to, 4 Fanconi anemia, complementation group S
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002801713.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely benign
(May 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209924.8
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 12531920, 25348012, 24728327, 15829246, 16267036, 15235020, 15726418, 22811390, 23192404, 22516946, 26913838, 18273839, 25782689, 16518693, 27527004, 15385441)
|
|
|
Benign
(Jul 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000887624.4
First in ClinVar: Mar 17, 2018 Last updated: Jan 06, 2024 |
|
|
|
Likely benign
(Oct 30, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185844.7
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
(May 29, 2002)
|
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: SCV000144092.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 5
Ethnicity/Population group: African
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: African American
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
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: SCV001550887.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRCA1 p.His476Arg variant was identified in 3 of 862 proband chromosomes (frequency: 0.003) from individuals or families with breast and or ovarian cancer and … (more)
The BRCA1 p.His476Arg variant was identified in 3 of 862 proband chromosomes (frequency: 0.003) from individuals or families with breast and or ovarian cancer and triple negative breast cancer cases; variant was not identified in 1362 control chromosomes from healthy individuals (McKean_Cowdin_2005_15726418, Rummel_2013_23192404). The variant was also identified in the following databases: dbSNP (ID: rs55720177) as “With other allele”, ClinVar (1x, as benign by Invitae, 4x as likely benign by Ambry Genetics, GeneDx, Counsyl, Quest Diagnostics, 1x as uncertain significance by BIC 1x ITMI), Clinvitae (4x, as benign and likely benign by ClinVar and Invitae), LOVD 3.0 (7x), UMD-LSDB (6 records, as neutral), BIC (9x). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, and Zhejiang Colon Cancer database. The variant was identified in control databases in 79 of 277056 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 70 of 24036 chromosomes (freq: 0.003), Latino in 9 of 34418 chromosomes (freq: 0.0003), while the variant was not observed in the Other, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant p.His476Arg has been reported to reside with a known deleterious mutation (BRCA1, 943ins10) (Judkins_2005_16267036). The p.His476Arg residue is not conserved in mammals 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 and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
|
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000084422.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant is associated with the following publications: (PMID: 12531920, 25348012, 24728327, 15829246, 16267036, 15235020, 15726418, 22811390, 23192404, 22516946, 26913838, 18273839, 25782689, 16518693, 27527004, 15385441)
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:
The BRCA1 p.His476Arg variant was identified in 3 of 862 proband chromosomes (frequency: 0.003) from individuals or families with breast and or ovarian cancer and triple negative breast cancer cases; variant was not identified in 1362 control chromosomes from healthy individuals (McKean_Cowdin_2005_15726418, Rummel_2013_23192404). The variant was also identified in the following databases: dbSNP (ID: rs55720177) as “With other allele”, ClinVar (1x, as benign by Invitae, 4x as likely benign by Ambry Genetics, GeneDx, Counsyl, Quest Diagnostics, 1x as uncertain significance by BIC 1x ITMI), Clinvitae (4x, as benign and likely benign by ClinVar and Invitae), LOVD 3.0 (7x), UMD-LSDB (6 records, as neutral), BIC (9x). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, and Zhejiang Colon Cancer database. The variant was identified in control databases in 79 of 277056 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 70 of 24036 chromosomes (freq: 0.003), Latino in 9 of 34418 chromosomes (freq: 0.0003), while the variant was not observed in the Other, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant p.His476Arg has been reported to reside with a known deleterious mutation (BRCA1, 943ins10) (Judkins_2005_16267036). The p.His476Arg residue is not conserved in mammals 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 and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
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:
Variant summary: The BRCA1 c.1427A>G (p.His476Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide located in the BRCA1, serine-rich domain (IPR025994) (InterPro). 3/5 in silico tools predict a damaging outcome for this variant. A functional study showed no dramatic effect on splicing for this variant (Anczukow_Genes Chromosomes and Cancer_2008). This variant was found in 34/121588 control chromosomes in the control population ExAc and in published studies, predominantly observed in the African subpopulation at a frequency of 0.00298 (31/10404). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has been reported in affected individuals via publications including one paper reporting the variant to co-occur with another deleterious BRCA1 variant, c.943ins10 (Judkins_2005) referenced in BIC, which also reports another individual with a co-occurring deleterious BRCA2 variant, c.5616_5620delAGTAA. This variant is found in two internal specimens co-occuring with pathogenic variants BRCA2 c.2957_2958insG and PMS2 c.2186_2187delTC. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Comment:
This variant is associated with the following publications: (PMID: 12531920, 25348012, 24728327, 15829246, 16267036, 15235020, 15726418, 22811390, 23192404, 22516946, 26913838, 18273839, 25782689, 16518693, 27527004, 15385441)
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:
The BRCA1 p.His476Arg variant was identified in 3 of 862 proband chromosomes (frequency: 0.003) from individuals or families with breast and or ovarian cancer and triple negative breast cancer cases; variant was not identified in 1362 control chromosomes from healthy individuals (McKean_Cowdin_2005_15726418, Rummel_2013_23192404). The variant was also identified in the following databases: dbSNP (ID: rs55720177) as “With other allele”, ClinVar (1x, as benign by Invitae, 4x as likely benign by Ambry Genetics, GeneDx, Counsyl, Quest Diagnostics, 1x as uncertain significance by BIC 1x ITMI), Clinvitae (4x, as benign and likely benign by ClinVar and Invitae), LOVD 3.0 (7x), UMD-LSDB (6 records, as neutral), BIC (9x). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, and Zhejiang Colon Cancer database. The variant was identified in control databases in 79 of 277056 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 70 of 24036 chromosomes (freq: 0.003), Latino in 9 of 34418 chromosomes (freq: 0.0003), while the variant was not observed in the Other, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant p.His476Arg has been reported to reside with a known deleterious mutation (BRCA1, 943ins10) (Judkins_2005_16267036). The p.His476Arg residue is not conserved in mammals 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 and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience. | Van der Merwe NC | Frontiers in genetics | 2022 | DOI: 10.3389/fgene.2022.834265 |
| Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations. | Martelotto LG | Genome biology | 2014 | PMID: 25348012 |
| Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
| Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer. | Rummel S | Breast cancer research and treatment | 2013 | PMID: 23192404 |
| BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. | Pennington KP | Cancer | 2013 | PMID: 22811390 |
| Germline BRCA1 mutations increase prostate cancer risk. | Leongamornlert D | British journal of cancer | 2012 | PMID: 22516946 |
| Unclassified variants identified in BRCA1 exon 11: Consequences on splicing. | Anczuków O | Genes, chromosomes & cancer | 2008 | PMID: 18273839 |
| 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 |
| Single nucleotide polymorphisms in clinical genetic testing: the characterization of the clinical significance of genetic variants and their application in clinical research for BRCA1. | Judkins T | Mutation research | 2005 | PMID: 15829246 |
| BRCA1 variants in a family study of African-American and Latina women. | McKean-Cowdin R | Human genetics | 2005 | PMID: 15726418 |
| 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 |
| Understanding missense mutations in the BRCA1 gene: an evolutionary approach. | Fleming MA | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12531920 |
| The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
| click to load more click to collapse | ||||
Text-mined citations for rs55720177 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated 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.