This variant is denoted BRCA1 c.4657T>A at the cDNA level, p.Leu1553Met (L1553M) at the protein level, and results in the change of a Leucine to a Methionine (TTG>ATG). Using alternate nomenclature, this variant would be defined as BRCA1 4776T>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Leu1553Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Leu1553Met occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is not located in a known functional domain (UniProt). While published in silico and evolutionary conservation analysis predicted that this variant is probably damaging (Pavlicek 2004), in-house in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Leu1553Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.4657T>A (p.Leu1553Met)
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.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(1); Likely benign(2)
Uncertain significance(4); Benign(1); Likely benign(2)
9
criteria provided, conflicting classifications
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.4657T>A (p.Leu1553Met)
Variation ID: 55254 Accession: VCV000055254.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43074349 (GRCh38) [ NCBI UCSC ] 17: 41226366 (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 1, 2014 Jul 23, 2024 Apr 4, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.4657T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Leu1553Met missense NM_001407571.1:c.4444T>A NP_001394500.1:p.Leu1482Met missense NM_001407581.1:c.4723T>A NP_001394510.1:p.Leu1575Met missense NM_001407582.1:c.4723T>A NP_001394511.1:p.Leu1575Met missense NM_001407583.1:c.4720T>A NP_001394512.1:p.Leu1574Met missense NM_001407585.1:c.4720T>A NP_001394514.1:p.Leu1574Met missense NM_001407587.1:c.4720T>A NP_001394516.1:p.Leu1574Met missense NM_001407590.1:c.4717T>A NP_001394519.1:p.Leu1573Met missense NM_001407591.1:c.4717T>A NP_001394520.1:p.Leu1573Met missense NM_001407593.1:c.4657T>A NP_001394522.1:p.Leu1553Met missense NM_001407594.1:c.4657T>A NP_001394523.1:p.Leu1553Met missense NM_001407596.1:c.4657T>A NP_001394525.1:p.Leu1553Met missense NM_001407597.1:c.4657T>A NP_001394526.1:p.Leu1553Met missense NM_001407598.1:c.4657T>A NP_001394527.1:p.Leu1553Met missense NM_001407602.1:c.4657T>A NP_001394531.1:p.Leu1553Met missense NM_001407603.1:c.4657T>A NP_001394532.1:p.Leu1553Met missense NM_001407605.1:c.4657T>A NP_001394534.1:p.Leu1553Met missense NM_001407610.1:c.4654T>A NP_001394539.1:p.Leu1552Met missense NM_001407611.1:c.4654T>A NP_001394540.1:p.Leu1552Met missense NM_001407612.1:c.4654T>A NP_001394541.1:p.Leu1552Met missense NM_001407613.1:c.4654T>A NP_001394542.1:p.Leu1552Met missense NM_001407614.1:c.4654T>A NP_001394543.1:p.Leu1552Met missense NM_001407615.1:c.4654T>A NP_001394544.1:p.Leu1552Met missense NM_001407616.1:c.4654T>A NP_001394545.1:p.Leu1552Met missense NM_001407617.1:c.4654T>A NP_001394546.1:p.Leu1552Met missense NM_001407618.1:c.4654T>A NP_001394547.1:p.Leu1552Met missense NM_001407619.1:c.4654T>A NP_001394548.1:p.Leu1552Met missense NM_001407620.1:c.4654T>A NP_001394549.1:p.Leu1552Met missense NM_001407621.1:c.4654T>A NP_001394550.1:p.Leu1552Met missense NM_001407622.1:c.4654T>A NP_001394551.1:p.Leu1552Met missense NM_001407623.1:c.4654T>A NP_001394552.1:p.Leu1552Met missense NM_001407624.1:c.4654T>A NP_001394553.1:p.Leu1552Met missense NM_001407625.1:c.4654T>A NP_001394554.1:p.Leu1552Met missense NM_001407626.1:c.4654T>A NP_001394555.1:p.Leu1552Met missense NM_001407627.1:c.4651T>A NP_001394556.1:p.Leu1551Met missense NM_001407628.1:c.4651T>A NP_001394557.1:p.Leu1551Met missense NM_001407629.1:c.4651T>A NP_001394558.1:p.Leu1551Met missense NM_001407630.1:c.4651T>A NP_001394559.1:p.Leu1551Met missense NM_001407631.1:c.4651T>A NP_001394560.1:p.Leu1551Met missense NM_001407632.1:c.4651T>A NP_001394561.1:p.Leu1551Met missense NM_001407633.1:c.4651T>A NP_001394562.1:p.Leu1551Met missense NM_001407634.1:c.4651T>A NP_001394563.1:p.Leu1551Met missense NM_001407635.1:c.4651T>A NP_001394564.1:p.Leu1551Met missense NM_001407636.1:c.4651T>A NP_001394565.1:p.Leu1551Met missense NM_001407637.1:c.4651T>A NP_001394566.1:p.Leu1551Met missense NM_001407638.1:c.4651T>A NP_001394567.1:p.Leu1551Met missense NM_001407639.1:c.4651T>A NP_001394568.1:p.Leu1551Met missense NM_001407640.1:c.4651T>A NP_001394569.1:p.Leu1551Met missense NM_001407641.1:c.4651T>A NP_001394570.1:p.Leu1551Met missense NM_001407642.1:c.4651T>A NP_001394571.1:p.Leu1551Met missense NM_001407644.1:c.4648T>A NP_001394573.1:p.Leu1550Met missense NM_001407645.1:c.4648T>A NP_001394574.1:p.Leu1550Met missense NM_001407646.1:c.4645T>A NP_001394575.1:p.Leu1549Met missense NM_001407647.1:c.4642T>A NP_001394576.1:p.Leu1548Met missense NM_001407648.1:c.4600T>A NP_001394577.1:p.Leu1534Met missense NM_001407649.1:c.4597T>A NP_001394578.1:p.Leu1533Met missense NM_001407652.1:c.4657T>A NP_001394581.1:p.Leu1553Met missense NM_001407653.1:c.4579T>A NP_001394582.1:p.Leu1527Met missense NM_001407654.1:c.4579T>A NP_001394583.1:p.Leu1527Met missense NM_001407655.1:c.4579T>A NP_001394584.1:p.Leu1527Met missense NM_001407656.1:c.4576T>A NP_001394585.1:p.Leu1526Met missense NM_001407657.1:c.4576T>A NP_001394586.1:p.Leu1526Met missense NM_001407658.1:c.4576T>A NP_001394587.1:p.Leu1526Met missense NM_001407659.1:c.4573T>A NP_001394588.1:p.Leu1525Met missense NM_001407660.1:c.4573T>A NP_001394589.1:p.Leu1525Met missense NM_001407661.1:c.4573T>A NP_001394590.1:p.Leu1525Met missense NM_001407662.1:c.4573T>A NP_001394591.1:p.Leu1525Met missense NM_001407663.1:c.4573T>A NP_001394592.1:p.Leu1525Met missense NM_001407664.1:c.4534T>A NP_001394593.1:p.Leu1512Met missense NM_001407665.1:c.4534T>A NP_001394594.1:p.Leu1512Met missense NM_001407666.1:c.4534T>A NP_001394595.1:p.Leu1512Met missense NM_001407667.1:c.4534T>A NP_001394596.1:p.Leu1512Met missense NM_001407668.1:c.4534T>A NP_001394597.1:p.Leu1512Met missense NM_001407669.1:c.4534T>A NP_001394598.1:p.Leu1512Met missense NM_001407670.1:c.4531T>A NP_001394599.1:p.Leu1511Met missense NM_001407671.1:c.4531T>A NP_001394600.1:p.Leu1511Met missense NM_001407672.1:c.4531T>A NP_001394601.1:p.Leu1511Met missense NM_001407673.1:c.4531T>A NP_001394602.1:p.Leu1511Met missense NM_001407674.1:c.4531T>A NP_001394603.1:p.Leu1511Met missense NM_001407675.1:c.4531T>A NP_001394604.1:p.Leu1511Met missense NM_001407676.1:c.4531T>A NP_001394605.1:p.Leu1511Met missense NM_001407677.1:c.4531T>A NP_001394606.1:p.Leu1511Met missense NM_001407678.1:c.4531T>A NP_001394607.1:p.Leu1511Met missense NM_001407679.1:c.4531T>A NP_001394608.1:p.Leu1511Met missense NM_001407680.1:c.4531T>A NP_001394609.1:p.Leu1511Met missense NM_001407681.1:c.4528T>A NP_001394610.1:p.Leu1510Met missense NM_001407682.1:c.4528T>A NP_001394611.1:p.Leu1510Met missense NM_001407683.1:c.4528T>A NP_001394612.1:p.Leu1510Met missense NM_001407684.1:c.4657T>A NP_001394613.1:p.Leu1553Met missense NM_001407685.1:c.4528T>A NP_001394614.1:p.Leu1510Met missense NM_001407686.1:c.4528T>A NP_001394615.1:p.Leu1510Met missense NM_001407687.1:c.4528T>A NP_001394616.1:p.Leu1510Met missense NM_001407688.1:c.4528T>A NP_001394617.1:p.Leu1510Met missense NM_001407689.1:c.4528T>A NP_001394618.1:p.Leu1510Met missense NM_001407690.1:c.4525T>A NP_001394619.1:p.Leu1509Met missense NM_001407691.1:c.4525T>A NP_001394620.1:p.Leu1509Met missense NM_001407692.1:c.4516T>A NP_001394621.1:p.Leu1506Met missense NM_001407694.1:c.4516T>A NP_001394623.1:p.Leu1506Met missense NM_001407695.1:c.4516T>A NP_001394624.1:p.Leu1506Met missense NM_001407696.1:c.4516T>A NP_001394625.1:p.Leu1506Met missense NM_001407697.1:c.4516T>A NP_001394626.1:p.Leu1506Met missense NM_001407698.1:c.4516T>A NP_001394627.1:p.Leu1506Met missense NM_001407724.1:c.4516T>A NP_001394653.1:p.Leu1506Met missense NM_001407725.1:c.4516T>A NP_001394654.1:p.Leu1506Met missense NM_001407726.1:c.4516T>A NP_001394655.1:p.Leu1506Met missense NM_001407727.1:c.4516T>A NP_001394656.1:p.Leu1506Met missense NM_001407728.1:c.4516T>A NP_001394657.1:p.Leu1506Met missense NM_001407729.1:c.4516T>A NP_001394658.1:p.Leu1506Met missense NM_001407730.1:c.4516T>A NP_001394659.1:p.Leu1506Met missense NM_001407731.1:c.4516T>A NP_001394660.1:p.Leu1506Met missense NM_001407732.1:c.4513T>A NP_001394661.1:p.Leu1505Met missense NM_001407733.1:c.4513T>A NP_001394662.1:p.Leu1505Met missense NM_001407734.1:c.4513T>A NP_001394663.1:p.Leu1505Met missense NM_001407735.1:c.4513T>A NP_001394664.1:p.Leu1505Met missense NM_001407736.1:c.4513T>A NP_001394665.1:p.Leu1505Met missense NM_001407737.1:c.4513T>A NP_001394666.1:p.Leu1505Met missense NM_001407738.1:c.4513T>A NP_001394667.1:p.Leu1505Met missense NM_001407739.1:c.4513T>A NP_001394668.1:p.Leu1505Met missense NM_001407740.1:c.4513T>A NP_001394669.1:p.Leu1505Met missense NM_001407741.1:c.4513T>A NP_001394670.1:p.Leu1505Met missense NM_001407742.1:c.4513T>A NP_001394671.1:p.Leu1505Met missense NM_001407743.1:c.4513T>A NP_001394672.1:p.Leu1505Met missense NM_001407744.1:c.4513T>A NP_001394673.1:p.Leu1505Met missense NM_001407745.1:c.4513T>A NP_001394674.1:p.Leu1505Met missense NM_001407746.1:c.4513T>A NP_001394675.1:p.Leu1505Met missense NM_001407747.1:c.4513T>A NP_001394676.1:p.Leu1505Met missense NM_001407748.1:c.4513T>A NP_001394677.1:p.Leu1505Met missense NM_001407749.1:c.4513T>A NP_001394678.1:p.Leu1505Met missense NM_001407750.1:c.4513T>A NP_001394679.1:p.Leu1505Met missense NM_001407751.1:c.4513T>A NP_001394680.1:p.Leu1505Met missense NM_001407752.1:c.4513T>A NP_001394681.1:p.Leu1505Met missense NM_001407838.1:c.4510T>A NP_001394767.1:p.Leu1504Met missense NM_001407839.1:c.4510T>A NP_001394768.1:p.Leu1504Met missense NM_001407841.1:c.4510T>A NP_001394770.1:p.Leu1504Met missense NM_001407842.1:c.4510T>A NP_001394771.1:p.Leu1504Met missense NM_001407843.1:c.4510T>A NP_001394772.1:p.Leu1504Met missense NM_001407844.1:c.4510T>A NP_001394773.1:p.Leu1504Met missense NM_001407845.1:c.4510T>A NP_001394774.1:p.Leu1504Met missense NM_001407846.1:c.4510T>A NP_001394775.1:p.Leu1504Met missense NM_001407847.1:c.4510T>A NP_001394776.1:p.Leu1504Met missense NM_001407848.1:c.4510T>A NP_001394777.1:p.Leu1504Met missense NM_001407849.1:c.4510T>A NP_001394778.1:p.Leu1504Met missense NM_001407850.1:c.4510T>A NP_001394779.1:p.Leu1504Met missense NM_001407851.1:c.4510T>A NP_001394780.1:p.Leu1504Met missense NM_001407852.1:c.4510T>A NP_001394781.1:p.Leu1504Met missense NM_001407853.1:c.4510T>A NP_001394782.1:p.Leu1504Met missense NM_001407854.1:c.4657T>A NP_001394783.1:p.Leu1553Met missense NM_001407858.1:c.4654T>A NP_001394787.1:p.Leu1552Met missense NM_001407859.1:c.4654T>A NP_001394788.1:p.Leu1552Met missense NM_001407860.1:c.4654T>A NP_001394789.1:p.Leu1552Met missense NM_001407861.1:c.4651T>A NP_001394790.1:p.Leu1551Met missense NM_001407862.1:c.4456T>A NP_001394791.1:p.Leu1486Met missense NM_001407863.1:c.4531T>A NP_001394792.1:p.Leu1511Met missense NM_001407874.1:c.4450T>A NP_001394803.1:p.Leu1484Met missense NM_001407875.1:c.4450T>A NP_001394804.1:p.Leu1484Met missense NM_001407879.1:c.4447T>A NP_001394808.1:p.Leu1483Met missense NM_001407881.1:c.4447T>A NP_001394810.1:p.Leu1483Met missense NM_001407882.1:c.4447T>A NP_001394811.1:p.Leu1483Met missense NM_001407884.1:c.4447T>A NP_001394813.1:p.Leu1483Met missense NM_001407885.1:c.4447T>A NP_001394814.1:p.Leu1483Met missense NM_001407886.1:c.4447T>A NP_001394815.1:p.Leu1483Met missense NM_001407887.1:c.4447T>A NP_001394816.1:p.Leu1483Met missense NM_001407889.1:c.4447T>A NP_001394818.1:p.Leu1483Met missense NM_001407894.1:c.4444T>A NP_001394823.1:p.Leu1482Met missense NM_001407895.1:c.4444T>A NP_001394824.1:p.Leu1482Met missense NM_001407896.1:c.4444T>A NP_001394825.1:p.Leu1482Met missense NM_001407897.1:c.4444T>A NP_001394826.1:p.Leu1482Met missense NM_001407898.1:c.4444T>A NP_001394827.1:p.Leu1482Met missense NM_001407899.1:c.4444T>A NP_001394828.1:p.Leu1482Met missense NM_001407900.1:c.4444T>A NP_001394829.1:p.Leu1482Met missense NM_001407902.1:c.4444T>A NP_001394831.1:p.Leu1482Met missense NM_001407904.1:c.4444T>A NP_001394833.1:p.Leu1482Met missense NM_001407906.1:c.4444T>A NP_001394835.1:p.Leu1482Met missense NM_001407907.1:c.4444T>A NP_001394836.1:p.Leu1482Met missense NM_001407908.1:c.4444T>A NP_001394837.1:p.Leu1482Met missense NM_001407909.1:c.4444T>A NP_001394838.1:p.Leu1482Met missense NM_001407910.1:c.4444T>A NP_001394839.1:p.Leu1482Met missense NM_001407915.1:c.4441T>A NP_001394844.1:p.Leu1481Met missense NM_001407916.1:c.4441T>A NP_001394845.1:p.Leu1481Met missense NM_001407917.1:c.4441T>A NP_001394846.1:p.Leu1481Met missense NM_001407918.1:c.4441T>A NP_001394847.1:p.Leu1481Met missense NM_001407919.1:c.4534T>A NP_001394848.1:p.Leu1512Met missense NM_001407920.1:c.4393T>A NP_001394849.1:p.Leu1465Met missense NM_001407921.1:c.4393T>A NP_001394850.1:p.Leu1465Met missense NM_001407922.1:c.4393T>A NP_001394851.1:p.Leu1465Met missense NM_001407923.1:c.4393T>A NP_001394852.1:p.Leu1465Met missense NM_001407924.1:c.4393T>A NP_001394853.1:p.Leu1465Met missense NM_001407925.1:c.4393T>A NP_001394854.1:p.Leu1465Met missense NM_001407926.1:c.4393T>A NP_001394855.1:p.Leu1465Met missense NM_001407927.1:c.4390T>A NP_001394856.1:p.Leu1464Met missense NM_001407928.1:c.4390T>A NP_001394857.1:p.Leu1464Met missense NM_001407929.1:c.4390T>A NP_001394858.1:p.Leu1464Met missense NM_001407930.1:c.4390T>A NP_001394859.1:p.Leu1464Met missense NM_001407931.1:c.4390T>A NP_001394860.1:p.Leu1464Met missense NM_001407932.1:c.4390T>A NP_001394861.1:p.Leu1464Met missense NM_001407933.1:c.4390T>A NP_001394862.1:p.Leu1464Met missense NM_001407934.1:c.4387T>A NP_001394863.1:p.Leu1463Met missense NM_001407935.1:c.4387T>A NP_001394864.1:p.Leu1463Met missense NM_001407936.1:c.4387T>A NP_001394865.1:p.Leu1463Met missense NM_001407937.1:c.4534T>A NP_001394866.1:p.Leu1512Met missense NM_001407938.1:c.4534T>A NP_001394867.1:p.Leu1512Met missense NM_001407939.1:c.4531T>A NP_001394868.1:p.Leu1511Met missense NM_001407940.1:c.4531T>A NP_001394869.1:p.Leu1511Met missense NM_001407941.1:c.4528T>A NP_001394870.1:p.Leu1510Met missense NM_001407942.1:c.4516T>A NP_001394871.1:p.Leu1506Met missense NM_001407943.1:c.4513T>A NP_001394872.1:p.Leu1505Met missense NM_001407944.1:c.4513T>A NP_001394873.1:p.Leu1505Met missense NM_001407945.1:c.4513T>A NP_001394874.1:p.Leu1505Met missense NM_001407946.1:c.4324T>A NP_001394875.1:p.Leu1442Met missense NM_001407947.1:c.4324T>A NP_001394876.1:p.Leu1442Met missense NM_001407948.1:c.4324T>A NP_001394877.1:p.Leu1442Met missense NM_001407949.1:c.4324T>A NP_001394878.1:p.Leu1442Met missense NM_001407950.1:c.4321T>A NP_001394879.1:p.Leu1441Met missense NM_001407951.1:c.4321T>A NP_001394880.1:p.Leu1441Met missense NM_001407952.1:c.4321T>A NP_001394881.1:p.Leu1441Met missense NM_001407953.1:c.4321T>A NP_001394882.1:p.Leu1441Met missense NM_001407954.1:c.4321T>A NP_001394883.1:p.Leu1441Met missense NM_001407955.1:c.4321T>A NP_001394884.1:p.Leu1441Met missense NM_001407956.1:c.4318T>A NP_001394885.1:p.Leu1440Met missense NM_001407957.1:c.4318T>A NP_001394886.1:p.Leu1440Met missense NM_001407958.1:c.4318T>A NP_001394887.1:p.Leu1440Met missense NM_001407959.1:c.4276T>A NP_001394888.1:p.Leu1426Met missense NM_001407960.1:c.4273T>A NP_001394889.1:p.Leu1425Met missense NM_001407962.1:c.4273T>A NP_001394891.1:p.Leu1425Met missense NM_001407963.1:c.4270T>A NP_001394892.1:p.Leu1424Met missense NM_001407965.1:c.4150T>A NP_001394894.1:p.Leu1384Met missense NM_001407966.1:c.3769T>A NP_001394895.1:p.Leu1257Met missense NM_001407967.1:c.3766T>A NP_001394896.1:p.Leu1256Met missense NM_001407968.1:c.2053T>A NP_001394897.1:p.Leu685Met missense NM_001407969.1:c.2050T>A NP_001394898.1:p.Leu684Met missense NM_001407970.1:c.1414T>A NP_001394899.1:p.Leu472Met missense NM_001407971.1:c.1414T>A NP_001394900.1:p.Leu472Met missense NM_001407972.1:c.1411T>A NP_001394901.1:p.Leu471Met missense NM_001407973.1:c.1348T>A NP_001394902.1:p.Leu450Met missense NM_001407974.1:c.1348T>A NP_001394903.1:p.Leu450Met missense NM_001407975.1:c.1348T>A NP_001394904.1:p.Leu450Met missense NM_001407976.1:c.1348T>A NP_001394905.1:p.Leu450Met missense NM_001407977.1:c.1348T>A NP_001394906.1:p.Leu450Met missense NM_001407978.1:c.1348T>A NP_001394907.1:p.Leu450Met missense NM_001407979.1:c.1345T>A NP_001394908.1:p.Leu449Met missense NM_001407980.1:c.1345T>A NP_001394909.1:p.Leu449Met missense NM_001407981.1:c.1345T>A NP_001394910.1:p.Leu449Met missense NM_001407982.1:c.1345T>A NP_001394911.1:p.Leu449Met missense NM_001407983.1:c.1345T>A NP_001394912.1:p.Leu449Met missense NM_001407984.1:c.1345T>A NP_001394913.1:p.Leu449Met missense NM_001407985.1:c.1345T>A NP_001394914.1:p.Leu449Met missense NM_001407986.1:c.1345T>A NP_001394915.1:p.Leu449Met missense NM_001407990.1:c.1345T>A NP_001394919.1:p.Leu449Met missense NM_001407991.1:c.1345T>A NP_001394920.1:p.Leu449Met missense NM_001407992.1:c.1345T>A NP_001394921.1:p.Leu449Met missense NM_001407993.1:c.1345T>A NP_001394922.1:p.Leu449Met missense NM_001408392.1:c.1342T>A NP_001395321.1:p.Leu448Met missense NM_001408396.1:c.1342T>A NP_001395325.1:p.Leu448Met missense NM_001408397.1:c.1342T>A NP_001395326.1:p.Leu448Met missense NM_001408398.1:c.1342T>A NP_001395327.1:p.Leu448Met missense NM_001408399.1:c.1342T>A NP_001395328.1:p.Leu448Met missense NM_001408400.1:c.1342T>A NP_001395329.1:p.Leu448Met missense NM_001408401.1:c.1342T>A NP_001395330.1:p.Leu448Met missense NM_001408402.1:c.1342T>A NP_001395331.1:p.Leu448Met missense NM_001408403.1:c.1342T>A NP_001395332.1:p.Leu448Met missense NM_001408404.1:c.1342T>A NP_001395333.1:p.Leu448Met missense NM_001408406.1:c.1339T>A NP_001395335.1:p.Leu447Met missense NM_001408407.1:c.1339T>A NP_001395336.1:p.Leu447Met missense NM_001408408.1:c.1339T>A NP_001395337.1:p.Leu447Met missense NM_001408409.1:c.1336T>A NP_001395338.1:p.Leu446Met missense NM_001408410.1:c.1273T>A NP_001395339.1:p.Leu425Met missense NM_001408411.1:c.1270T>A NP_001395340.1:p.Leu424Met missense NM_001408412.1:c.1267T>A NP_001395341.1:p.Leu423Met missense NM_001408413.1:c.1267T>A NP_001395342.1:p.Leu423Met missense NM_001408414.1:c.1267T>A NP_001395343.1:p.Leu423Met missense NM_001408415.1:c.1267T>A NP_001395344.1:p.Leu423Met missense NM_001408416.1:c.1267T>A NP_001395345.1:p.Leu423Met missense NM_001408418.1:c.1231T>A NP_001395347.1:p.Leu411Met missense NM_001408419.1:c.1231T>A NP_001395348.1:p.Leu411Met missense NM_001408420.1:c.1231T>A NP_001395349.1:p.Leu411Met missense NM_001408421.1:c.1228T>A NP_001395350.1:p.Leu410Met missense NM_001408422.1:c.1228T>A NP_001395351.1:p.Leu410Met missense NM_001408423.1:c.1228T>A NP_001395352.1:p.Leu410Met missense NM_001408424.1:c.1228T>A NP_001395353.1:p.Leu410Met missense NM_001408425.1:c.1225T>A NP_001395354.1:p.Leu409Met missense NM_001408426.1:c.1225T>A NP_001395355.1:p.Leu409Met missense NM_001408427.1:c.1225T>A NP_001395356.1:p.Leu409Met missense NM_001408428.1:c.1225T>A NP_001395357.1:p.Leu409Met missense NM_001408429.1:c.1225T>A NP_001395358.1:p.Leu409Met missense NM_001408430.1:c.1225T>A NP_001395359.1:p.Leu409Met missense NM_001408431.1:c.1225T>A NP_001395360.1:p.Leu409Met missense NM_001408432.1:c.1222T>A NP_001395361.1:p.Leu408Met missense NM_001408433.1:c.1222T>A NP_001395362.1:p.Leu408Met missense NM_001408434.1:c.1222T>A NP_001395363.1:p.Leu408Met missense NM_001408435.1:c.1222T>A NP_001395364.1:p.Leu408Met missense NM_001408436.1:c.1222T>A NP_001395365.1:p.Leu408Met missense NM_001408437.1:c.1222T>A NP_001395366.1:p.Leu408Met missense NM_001408438.1:c.1222T>A NP_001395367.1:p.Leu408Met missense NM_001408439.1:c.1222T>A NP_001395368.1:p.Leu408Met missense NM_001408440.1:c.1222T>A NP_001395369.1:p.Leu408Met missense NM_001408441.1:c.1222T>A NP_001395370.1:p.Leu408Met missense NM_001408442.1:c.1222T>A NP_001395371.1:p.Leu408Met missense NM_001408443.1:c.1222T>A NP_001395372.1:p.Leu408Met missense NM_001408444.1:c.1222T>A NP_001395373.1:p.Leu408Met missense NM_001408445.1:c.1219T>A NP_001395374.1:p.Leu407Met missense NM_001408446.1:c.1219T>A NP_001395375.1:p.Leu407Met missense NM_001408447.1:c.1219T>A NP_001395376.1:p.Leu407Met missense NM_001408448.1:c.1219T>A NP_001395377.1:p.Leu407Met missense NM_001408450.1:c.1219T>A NP_001395379.1:p.Leu407Met missense NM_001408451.1:c.1213T>A NP_001395380.1:p.Leu405Met missense NM_001408452.1:c.1207T>A NP_001395381.1:p.Leu403Met missense NM_001408453.1:c.1207T>A NP_001395382.1:p.Leu403Met missense NM_001408454.1:c.1207T>A NP_001395383.1:p.Leu403Met missense NM_001408455.1:c.1207T>A NP_001395384.1:p.Leu403Met missense NM_001408456.1:c.1207T>A NP_001395385.1:p.Leu403Met missense NM_001408457.1:c.1207T>A NP_001395386.1:p.Leu403Met missense NM_001408458.1:c.1204T>A NP_001395387.1:p.Leu402Met missense NM_001408459.1:c.1204T>A NP_001395388.1:p.Leu402Met missense NM_001408460.1:c.1204T>A NP_001395389.1:p.Leu402Met missense NM_001408461.1:c.1204T>A NP_001395390.1:p.Leu402Met missense NM_001408462.1:c.1204T>A NP_001395391.1:p.Leu402Met missense NM_001408463.1:c.1204T>A NP_001395392.1:p.Leu402Met missense NM_001408464.1:c.1204T>A NP_001395393.1:p.Leu402Met missense NM_001408465.1:c.1204T>A NP_001395394.1:p.Leu402Met missense NM_001408466.1:c.1204T>A NP_001395395.1:p.Leu402Met missense NM_001408467.1:c.1204T>A NP_001395396.1:p.Leu402Met missense NM_001408468.1:c.1201T>A NP_001395397.1:p.Leu401Met missense NM_001408469.1:c.1201T>A NP_001395398.1:p.Leu401Met missense NM_001408470.1:c.1201T>A NP_001395399.1:p.Leu401Met missense NM_001408472.1:c.1345T>A NP_001395401.1:p.Leu449Met missense NM_001408473.1:c.1342T>A NP_001395402.1:p.Leu448Met missense NM_001408474.1:c.1147T>A NP_001395403.1:p.Leu383Met missense NM_001408475.1:c.1144T>A NP_001395404.1:p.Leu382Met missense NM_001408476.1:c.1144T>A NP_001395405.1:p.Leu382Met missense NM_001408478.1:c.1138T>A NP_001395407.1:p.Leu380Met missense NM_001408479.1:c.1138T>A NP_001395408.1:p.Leu380Met missense NM_001408480.1:c.1138T>A NP_001395409.1:p.Leu380Met missense NM_001408481.1:c.1135T>A NP_001395410.1:p.Leu379Met missense NM_001408482.1:c.1135T>A NP_001395411.1:p.Leu379Met missense NM_001408483.1:c.1135T>A NP_001395412.1:p.Leu379Met missense NM_001408484.1:c.1135T>A NP_001395413.1:p.Leu379Met missense NM_001408485.1:c.1135T>A NP_001395414.1:p.Leu379Met missense NM_001408489.1:c.1135T>A NP_001395418.1:p.Leu379Met missense NM_001408490.1:c.1135T>A NP_001395419.1:p.Leu379Met missense NM_001408491.1:c.1135T>A NP_001395420.1:p.Leu379Met missense NM_001408492.1:c.1132T>A NP_001395421.1:p.Leu378Met missense NM_001408493.1:c.1132T>A NP_001395422.1:p.Leu378Met missense NM_001408494.1:c.1108T>A NP_001395423.1:p.Leu370Met missense NM_001408495.1:c.1102T>A NP_001395424.1:p.Leu368Met missense NM_001408496.1:c.1084T>A NP_001395425.1:p.Leu362Met missense NM_001408497.1:c.1084T>A NP_001395426.1:p.Leu362Met missense NM_001408498.1:c.1084T>A NP_001395427.1:p.Leu362Met missense NM_001408499.1:c.1084T>A NP_001395428.1:p.Leu362Met missense NM_001408500.1:c.1084T>A NP_001395429.1:p.Leu362Met missense NM_001408501.1:c.1084T>A NP_001395430.1:p.Leu362Met missense NM_001408502.1:c.1081T>A NP_001395431.1:p.Leu361Met missense NM_001408503.1:c.1081T>A NP_001395432.1:p.Leu361Met missense NM_001408504.1:c.1081T>A NP_001395433.1:p.Leu361Met missense NM_001408505.1:c.1078T>A NP_001395434.1:p.Leu360Met missense NM_001408506.1:c.1021T>A NP_001395435.1:p.Leu341Met missense NM_001408507.1:c.1018T>A NP_001395436.1:p.Leu340Met missense NM_001408508.1:c.1009T>A NP_001395437.1:p.Leu337Met missense NM_001408509.1:c.1006T>A NP_001395438.1:p.Leu336Met missense NM_001408510.1:c.967T>A NP_001395439.1:p.Leu323Met missense NM_001408511.1:c.964T>A NP_001395440.1:p.Leu322Met missense NM_001408512.1:c.844T>A NP_001395441.1:p.Leu282Met missense NM_007297.4:c.4516T>A NP_009228.2:p.Leu1506Met missense NM_007298.4:c.1345T>A NP_009229.2:p.Leu449Met missense NM_007299.4:c.1345T>A NP_009230.2:p.Leu449Met missense NM_007300.4:c.4720T>A NP_009231.2:p.Leu1574Met missense NM_007304.2:c.1345T>A NP_009235.2:p.Leu449Met missense NR_027676.2:n.4834T>A non-coding transcript variant NC_000017.11:g.43074349A>T NC_000017.10:g.41226366A>T NG_005905.2:g.143635T>A LRG_292:g.143635T>A LRG_292t1:c.4657T>A LRG_292p1:p.Leu1553Met U14680.1:n.4776T>A - Protein change
- L1553M, L1506M, L449M, L1574M, L1384M, L1505M, L1550M, L1575M, L282M, L368M, L378M, L380M, L446M, L448M, L450M, L684M, L1256M, L1425M, L1426M, L1440M, L1442M, L1463M, L1464M, L1484M, L1511M, L1533M, L1534M, L1549M, L322M, L336M, L340M, L341M, L370M, L408M, L411M, L423M, L425M, L685M, L1424M, L1441M, L1486M, L1504M, L1509M, L1510M, L1527M, L1548M, L1551M, L1573M, L360M, L362M, L379M, L382M, L401M, L403M, L409M, L410M, L471M, L472M, L1257M, L1465M, L1481M, L1482M, L1483M, L1512M, L1525M, L1526M, L1552M, L323M, L337M, L361M, L383M, L402M, L405M, L407M, L424M, L447M
- Other names
-
p.L1553M:TTG>ATG
4776T>A
- Canonical SPDI
- NC_000017.11:43074348:A:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 |
13040 | 14846 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 4, 2024 | RCV000112375.11 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 3, 2022 | RCV000164710.15 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 24, 2023 | RCV000212184.10 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 28, 2024 | RCV001364498.12 |
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
(Jul 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785404.2
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
|
|
|
Uncertain significance
(Jul 10, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000210183.13
First in ClinVar: Feb 24, 2015 Last updated: Jun 01, 2016 |
Comment:
This variant is denoted BRCA1 c.4657T>A at the cDNA level, p.Leu1553Met (L1553M) at the protein level, and results in the change of a Leucine to … (more)
This variant is denoted BRCA1 c.4657T>A at the cDNA level, p.Leu1553Met (L1553M) at the protein level, and results in the change of a Leucine to a Methionine (TTG>ATG). Using alternate nomenclature, this variant would be defined as BRCA1 4776T>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Leu1553Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Leu1553Met occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is not located in a known functional domain (UniProt). While published in silico and evolutionary conservation analysis predicted that this variant is probably damaging (Pavlicek 2004), in-house in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Leu1553Met is pathogenic or benign. We consider it to be a variant of uncertain significance. (less)
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Likely benign
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001560651.3
First in ClinVar: Apr 13, 2021 Last updated: Feb 20, 2024 |
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Benign
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV005083642.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants … (more)
This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant been observed in trans with a known pathogenic variant in one or more individuals. Compound heterozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality. (less)
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Uncertain significance
(Aug 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004219413.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, … (more)
To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000004 (1/251230 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Dec 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004360160.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces leucine with methionine at codon 1553 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces leucine with methionine at codon 1553 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.1391 and 0.4284, respectively (PMID: 31131967). This variant has been identified in 1/251230 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Aug 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000215379.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.L1553M variant (also known as c.4657T>A), located in coding exon 13 of the BRCA1 gene, results from a T to A substitution at nucleotide … (more)
The p.L1553M variant (also known as c.4657T>A), located in coding exon 13 of the BRCA1 gene, results from a T to A substitution at nucleotide position 4657. The leucine at codon 1553 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Dec 23, 2003)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145142.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, English, Scottish
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Uncertain significance
(May 08, 2009)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000297614.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
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Comment:
Comment:
This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant been observed in trans with a known pathogenic variant in one or more individuals. Compound heterozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality.
Comment:
To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000004 (1/251230 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces leucine with methionine at codon 1553 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.1391 and 0.4284, respectively (PMID: 31131967). This variant has been identified in 1/251230 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.L1553M variant (also known as c.4657T>A), located in coding exon 13 of the BRCA1 gene, results from a T to A substitution at nucleotide position 4657. The leucine at codon 1553 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This variant is denoted BRCA1 c.4657T>A at the cDNA level, p.Leu1553Met (L1553M) at the protein level, and results in the change of a Leucine to a Methionine (TTG>ATG). Using alternate nomenclature, this variant would be defined as BRCA1 4776T>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Leu1553Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Leu1553Met occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is not located in a known functional domain (UniProt). While published in silico and evolutionary conservation analysis predicted that this variant is probably damaging (Pavlicek 2004), in-house in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Leu1553Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Comment:
This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant been observed in trans with a known pathogenic variant in one or more individuals. Compound heterozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality.
Comment:
To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000004 (1/251230 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces leucine with methionine at codon 1553 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.1391 and 0.4284, respectively (PMID: 31131967). This variant has been identified in 1/251230 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.L1553M variant (also known as c.4657T>A), located in coding exon 13 of the BRCA1 gene, results from a T to A substitution at nucleotide position 4657. The leucine at codon 1553 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. | Parsons MT | Human mutation | 2019 | PMID: 31131967 |
| Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Text-mined citations for rs80357431 ...
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 27, 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.