This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 1495 of the BRCA1 protein (p.Arg1495Met). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80357389, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 10571952, 10923033, 22144684, 23096355, 24607278). It has also been observed to segregate with disease in related individuals. This variant is also known as 4603G>T and c.4547G>T. ClinVar contains an entry for this variant (Variation ID: 37598). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 13 and introduces a premature termination codon (PMID: 10571952, 12915465, 21120943, 24607278; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.4484G>T (p.Arg1495Met)
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.
(24)
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.
Pathogenic
24
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.4484G>T (p.Arg1495Met)
Variation ID: 37598 Accession: VCV000037598.75
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43076488 (GRCh38) [ NCBI UCSC ] 17: 41228505 (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 Jun 17, 2024 Mar 26, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.4484G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Arg1495Met missense NM_001407571.1:c.4271G>T NP_001394500.1:p.Arg1424Met missense NM_001407581.1:c.4550G>T NP_001394510.1:p.Arg1517Met missense NM_001407582.1:c.4550G>T NP_001394511.1:p.Arg1517Met missense NM_001407583.1:c.4547G>T NP_001394512.1:p.Arg1516Met missense NM_001407585.1:c.4547G>T NP_001394514.1:p.Arg1516Met missense NM_001407587.1:c.4547G>T NP_001394516.1:p.Arg1516Met missense NM_001407590.1:c.4544G>T NP_001394519.1:p.Arg1515Met missense NM_001407591.1:c.4544G>T NP_001394520.1:p.Arg1515Met missense NM_001407593.1:c.4484G>T NP_001394522.1:p.Arg1495Met missense NM_001407594.1:c.4484G>T NP_001394523.1:p.Arg1495Met missense NM_001407596.1:c.4484G>T NP_001394525.1:p.Arg1495Met missense NM_001407597.1:c.4484G>T NP_001394526.1:p.Arg1495Met missense NM_001407598.1:c.4484G>T NP_001394527.1:p.Arg1495Met missense NM_001407602.1:c.4484G>T NP_001394531.1:p.Arg1495Met missense NM_001407603.1:c.4484G>T NP_001394532.1:p.Arg1495Met missense NM_001407605.1:c.4484G>T NP_001394534.1:p.Arg1495Met missense NM_001407610.1:c.4481G>T NP_001394539.1:p.Arg1494Met missense NM_001407611.1:c.4481G>T NP_001394540.1:p.Arg1494Met missense NM_001407612.1:c.4481G>T NP_001394541.1:p.Arg1494Met missense NM_001407613.1:c.4481G>T NP_001394542.1:p.Arg1494Met missense NM_001407614.1:c.4481G>T NP_001394543.1:p.Arg1494Met missense NM_001407615.1:c.4481G>T NP_001394544.1:p.Arg1494Met missense NM_001407616.1:c.4481G>T NP_001394545.1:p.Arg1494Met missense NM_001407617.1:c.4481G>T NP_001394546.1:p.Arg1494Met missense NM_001407618.1:c.4481G>T NP_001394547.1:p.Arg1494Met missense NM_001407619.1:c.4481G>T NP_001394548.1:p.Arg1494Met missense NM_001407620.1:c.4481G>T NP_001394549.1:p.Arg1494Met missense NM_001407621.1:c.4481G>T NP_001394550.1:p.Arg1494Met missense NM_001407622.1:c.4481G>T NP_001394551.1:p.Arg1494Met missense NM_001407623.1:c.4481G>T NP_001394552.1:p.Arg1494Met missense NM_001407624.1:c.4481G>T NP_001394553.1:p.Arg1494Met missense NM_001407625.1:c.4481G>T NP_001394554.1:p.Arg1494Met missense NM_001407626.1:c.4481G>T NP_001394555.1:p.Arg1494Met missense NM_001407627.1:c.4478G>T NP_001394556.1:p.Arg1493Met missense NM_001407628.1:c.4478G>T NP_001394557.1:p.Arg1493Met missense NM_001407629.1:c.4478G>T NP_001394558.1:p.Arg1493Met missense NM_001407630.1:c.4478G>T NP_001394559.1:p.Arg1493Met missense NM_001407631.1:c.4478G>T NP_001394560.1:p.Arg1493Met missense NM_001407632.1:c.4478G>T NP_001394561.1:p.Arg1493Met missense NM_001407633.1:c.4478G>T NP_001394562.1:p.Arg1493Met missense NM_001407634.1:c.4478G>T NP_001394563.1:p.Arg1493Met missense NM_001407635.1:c.4478G>T NP_001394564.1:p.Arg1493Met missense NM_001407636.1:c.4478G>T NP_001394565.1:p.Arg1493Met missense NM_001407637.1:c.4478G>T NP_001394566.1:p.Arg1493Met missense NM_001407638.1:c.4478G>T NP_001394567.1:p.Arg1493Met missense NM_001407639.1:c.4478G>T NP_001394568.1:p.Arg1493Met missense NM_001407640.1:c.4478G>T NP_001394569.1:p.Arg1493Met missense NM_001407641.1:c.4478G>T NP_001394570.1:p.Arg1493Met missense NM_001407642.1:c.4478G>T NP_001394571.1:p.Arg1493Met missense NM_001407644.1:c.4475G>T NP_001394573.1:p.Arg1492Met missense NM_001407645.1:c.4475G>T NP_001394574.1:p.Arg1492Met missense NM_001407646.1:c.4472G>T NP_001394575.1:p.Arg1491Met missense NM_001407647.1:c.4469G>T NP_001394576.1:p.Arg1490Met missense NM_001407648.1:c.4427G>T NP_001394577.1:p.Arg1476Met missense NM_001407649.1:c.4424G>T NP_001394578.1:p.Arg1475Met missense NM_001407652.1:c.4484G>T NP_001394581.1:p.Arg1495Met missense NM_001407653.1:c.4406G>T NP_001394582.1:p.Arg1469Met missense NM_001407654.1:c.4406G>T NP_001394583.1:p.Arg1469Met missense NM_001407655.1:c.4406G>T NP_001394584.1:p.Arg1469Met missense NM_001407656.1:c.4403G>T NP_001394585.1:p.Arg1468Met missense NM_001407657.1:c.4403G>T NP_001394586.1:p.Arg1468Met missense NM_001407658.1:c.4403G>T NP_001394587.1:p.Arg1468Met missense NM_001407659.1:c.4400G>T NP_001394588.1:p.Arg1467Met missense NM_001407660.1:c.4400G>T NP_001394589.1:p.Arg1467Met missense NM_001407661.1:c.4400G>T NP_001394590.1:p.Arg1467Met missense NM_001407662.1:c.4400G>T NP_001394591.1:p.Arg1467Met missense NM_001407663.1:c.4400G>T NP_001394592.1:p.Arg1467Met missense NM_001407664.1:c.4361G>T NP_001394593.1:p.Arg1454Met missense NM_001407665.1:c.4361G>T NP_001394594.1:p.Arg1454Met missense NM_001407666.1:c.4361G>T NP_001394595.1:p.Arg1454Met missense NM_001407667.1:c.4361G>T NP_001394596.1:p.Arg1454Met missense NM_001407668.1:c.4361G>T NP_001394597.1:p.Arg1454Met missense NM_001407669.1:c.4361G>T NP_001394598.1:p.Arg1454Met missense NM_001407670.1:c.4358G>T NP_001394599.1:p.Arg1453Met missense NM_001407671.1:c.4358G>T NP_001394600.1:p.Arg1453Met missense NM_001407672.1:c.4358G>T NP_001394601.1:p.Arg1453Met missense NM_001407673.1:c.4358G>T NP_001394602.1:p.Arg1453Met missense NM_001407674.1:c.4358G>T NP_001394603.1:p.Arg1453Met missense NM_001407675.1:c.4358G>T NP_001394604.1:p.Arg1453Met missense NM_001407676.1:c.4358G>T NP_001394605.1:p.Arg1453Met missense NM_001407677.1:c.4358G>T NP_001394606.1:p.Arg1453Met missense NM_001407678.1:c.4358G>T NP_001394607.1:p.Arg1453Met missense NM_001407679.1:c.4358G>T NP_001394608.1:p.Arg1453Met missense NM_001407680.1:c.4358G>T NP_001394609.1:p.Arg1453Met missense NM_001407681.1:c.4355G>T NP_001394610.1:p.Arg1452Met missense NM_001407682.1:c.4355G>T NP_001394611.1:p.Arg1452Met missense NM_001407683.1:c.4355G>T NP_001394612.1:p.Arg1452Met missense NM_001407684.1:c.4484G>T NP_001394613.1:p.Arg1495Met missense NM_001407685.1:c.4355G>T NP_001394614.1:p.Arg1452Met missense NM_001407686.1:c.4355G>T NP_001394615.1:p.Arg1452Met missense NM_001407687.1:c.4355G>T NP_001394616.1:p.Arg1452Met missense NM_001407688.1:c.4355G>T NP_001394617.1:p.Arg1452Met missense NM_001407689.1:c.4355G>T NP_001394618.1:p.Arg1452Met missense NM_001407690.1:c.4352G>T NP_001394619.1:p.Arg1451Met missense NM_001407691.1:c.4352G>T NP_001394620.1:p.Arg1451Met missense NM_001407692.1:c.4343G>T NP_001394621.1:p.Arg1448Met missense NM_001407694.1:c.4343G>T NP_001394623.1:p.Arg1448Met missense NM_001407695.1:c.4343G>T NP_001394624.1:p.Arg1448Met missense NM_001407696.1:c.4343G>T NP_001394625.1:p.Arg1448Met missense NM_001407697.1:c.4343G>T NP_001394626.1:p.Arg1448Met missense NM_001407698.1:c.4343G>T NP_001394627.1:p.Arg1448Met missense NM_001407724.1:c.4343G>T NP_001394653.1:p.Arg1448Met missense NM_001407725.1:c.4343G>T NP_001394654.1:p.Arg1448Met missense NM_001407726.1:c.4343G>T NP_001394655.1:p.Arg1448Met missense NM_001407727.1:c.4343G>T NP_001394656.1:p.Arg1448Met missense NM_001407728.1:c.4343G>T NP_001394657.1:p.Arg1448Met missense NM_001407729.1:c.4343G>T NP_001394658.1:p.Arg1448Met missense NM_001407730.1:c.4343G>T NP_001394659.1:p.Arg1448Met missense NM_001407731.1:c.4343G>T NP_001394660.1:p.Arg1448Met missense NM_001407732.1:c.4340G>T NP_001394661.1:p.Arg1447Met missense NM_001407733.1:c.4340G>T NP_001394662.1:p.Arg1447Met missense NM_001407734.1:c.4340G>T NP_001394663.1:p.Arg1447Met missense NM_001407735.1:c.4340G>T NP_001394664.1:p.Arg1447Met missense NM_001407736.1:c.4340G>T NP_001394665.1:p.Arg1447Met missense NM_001407737.1:c.4340G>T NP_001394666.1:p.Arg1447Met missense NM_001407738.1:c.4340G>T NP_001394667.1:p.Arg1447Met missense NM_001407739.1:c.4340G>T NP_001394668.1:p.Arg1447Met missense NM_001407740.1:c.4340G>T NP_001394669.1:p.Arg1447Met missense NM_001407741.1:c.4340G>T NP_001394670.1:p.Arg1447Met missense NM_001407742.1:c.4340G>T NP_001394671.1:p.Arg1447Met missense NM_001407743.1:c.4340G>T NP_001394672.1:p.Arg1447Met missense NM_001407744.1:c.4340G>T NP_001394673.1:p.Arg1447Met missense NM_001407745.1:c.4340G>T NP_001394674.1:p.Arg1447Met missense NM_001407746.1:c.4340G>T NP_001394675.1:p.Arg1447Met missense NM_001407747.1:c.4340G>T NP_001394676.1:p.Arg1447Met missense NM_001407748.1:c.4340G>T NP_001394677.1:p.Arg1447Met missense NM_001407749.1:c.4340G>T NP_001394678.1:p.Arg1447Met missense NM_001407750.1:c.4340G>T NP_001394679.1:p.Arg1447Met missense NM_001407751.1:c.4340G>T NP_001394680.1:p.Arg1447Met missense NM_001407752.1:c.4340G>T NP_001394681.1:p.Arg1447Met missense NM_001407838.1:c.4337G>T NP_001394767.1:p.Arg1446Met missense NM_001407839.1:c.4337G>T NP_001394768.1:p.Arg1446Met missense NM_001407841.1:c.4337G>T NP_001394770.1:p.Arg1446Met missense NM_001407842.1:c.4337G>T NP_001394771.1:p.Arg1446Met missense NM_001407843.1:c.4337G>T NP_001394772.1:p.Arg1446Met missense NM_001407844.1:c.4337G>T NP_001394773.1:p.Arg1446Met missense NM_001407845.1:c.4337G>T NP_001394774.1:p.Arg1446Met missense NM_001407846.1:c.4337G>T NP_001394775.1:p.Arg1446Met missense NM_001407847.1:c.4337G>T NP_001394776.1:p.Arg1446Met missense NM_001407848.1:c.4337G>T NP_001394777.1:p.Arg1446Met missense NM_001407849.1:c.4337G>T NP_001394778.1:p.Arg1446Met missense NM_001407850.1:c.4337G>T NP_001394779.1:p.Arg1446Met missense NM_001407851.1:c.4337G>T NP_001394780.1:p.Arg1446Met missense NM_001407852.1:c.4337G>T NP_001394781.1:p.Arg1446Met missense NM_001407853.1:c.4337G>T NP_001394782.1:p.Arg1446Met missense NM_001407854.1:c.4484G>T NP_001394783.1:p.Arg1495Met missense NM_001407858.1:c.4481G>T NP_001394787.1:p.Arg1494Met missense NM_001407859.1:c.4481G>T NP_001394788.1:p.Arg1494Met missense NM_001407860.1:c.4481G>T NP_001394789.1:p.Arg1494Met missense NM_001407861.1:c.4478G>T NP_001394790.1:p.Arg1493Met missense NM_001407862.1:c.4283G>T NP_001394791.1:p.Arg1428Met missense NM_001407863.1:c.4358G>T NP_001394792.1:p.Arg1453Met missense NM_001407874.1:c.4277G>T NP_001394803.1:p.Arg1426Met missense NM_001407875.1:c.4277G>T NP_001394804.1:p.Arg1426Met missense NM_001407879.1:c.4274G>T NP_001394808.1:p.Arg1425Met missense NM_001407881.1:c.4274G>T NP_001394810.1:p.Arg1425Met missense NM_001407882.1:c.4274G>T NP_001394811.1:p.Arg1425Met missense NM_001407884.1:c.4274G>T NP_001394813.1:p.Arg1425Met missense NM_001407885.1:c.4274G>T NP_001394814.1:p.Arg1425Met missense NM_001407886.1:c.4274G>T NP_001394815.1:p.Arg1425Met missense NM_001407887.1:c.4274G>T NP_001394816.1:p.Arg1425Met missense NM_001407889.1:c.4274G>T NP_001394818.1:p.Arg1425Met missense NM_001407894.1:c.4271G>T NP_001394823.1:p.Arg1424Met missense NM_001407895.1:c.4271G>T NP_001394824.1:p.Arg1424Met missense NM_001407896.1:c.4271G>T NP_001394825.1:p.Arg1424Met missense NM_001407897.1:c.4271G>T NP_001394826.1:p.Arg1424Met missense NM_001407898.1:c.4271G>T NP_001394827.1:p.Arg1424Met missense NM_001407899.1:c.4271G>T NP_001394828.1:p.Arg1424Met missense NM_001407900.1:c.4271G>T NP_001394829.1:p.Arg1424Met missense NM_001407902.1:c.4271G>T NP_001394831.1:p.Arg1424Met missense NM_001407904.1:c.4271G>T NP_001394833.1:p.Arg1424Met missense NM_001407906.1:c.4271G>T NP_001394835.1:p.Arg1424Met missense NM_001407907.1:c.4271G>T NP_001394836.1:p.Arg1424Met missense NM_001407908.1:c.4271G>T NP_001394837.1:p.Arg1424Met missense NM_001407909.1:c.4271G>T NP_001394838.1:p.Arg1424Met missense NM_001407910.1:c.4271G>T NP_001394839.1:p.Arg1424Met missense NM_001407915.1:c.4268G>T NP_001394844.1:p.Arg1423Met missense NM_001407916.1:c.4268G>T NP_001394845.1:p.Arg1423Met missense NM_001407917.1:c.4268G>T NP_001394846.1:p.Arg1423Met missense NM_001407918.1:c.4268G>T NP_001394847.1:p.Arg1423Met missense NM_001407919.1:c.4361G>T NP_001394848.1:p.Arg1454Met missense NM_001407920.1:c.4220G>T NP_001394849.1:p.Arg1407Met missense NM_001407921.1:c.4220G>T NP_001394850.1:p.Arg1407Met missense NM_001407922.1:c.4220G>T NP_001394851.1:p.Arg1407Met missense NM_001407923.1:c.4220G>T NP_001394852.1:p.Arg1407Met missense NM_001407924.1:c.4220G>T NP_001394853.1:p.Arg1407Met missense NM_001407925.1:c.4220G>T NP_001394854.1:p.Arg1407Met missense NM_001407926.1:c.4220G>T NP_001394855.1:p.Arg1407Met missense NM_001407927.1:c.4217G>T NP_001394856.1:p.Arg1406Met missense NM_001407928.1:c.4217G>T NP_001394857.1:p.Arg1406Met missense NM_001407929.1:c.4217G>T NP_001394858.1:p.Arg1406Met missense NM_001407930.1:c.4217G>T NP_001394859.1:p.Arg1406Met missense NM_001407931.1:c.4217G>T NP_001394860.1:p.Arg1406Met missense NM_001407932.1:c.4217G>T NP_001394861.1:p.Arg1406Met missense NM_001407933.1:c.4217G>T NP_001394862.1:p.Arg1406Met missense NM_001407934.1:c.4214G>T NP_001394863.1:p.Arg1405Met missense NM_001407935.1:c.4214G>T NP_001394864.1:p.Arg1405Met missense NM_001407936.1:c.4214G>T NP_001394865.1:p.Arg1405Met missense NM_001407937.1:c.4361G>T NP_001394866.1:p.Arg1454Met missense NM_001407938.1:c.4361G>T NP_001394867.1:p.Arg1454Met missense NM_001407939.1:c.4358G>T NP_001394868.1:p.Arg1453Met missense NM_001407940.1:c.4358G>T NP_001394869.1:p.Arg1453Met missense NM_001407941.1:c.4355G>T NP_001394870.1:p.Arg1452Met missense NM_001407942.1:c.4343G>T NP_001394871.1:p.Arg1448Met missense NM_001407943.1:c.4340G>T NP_001394872.1:p.Arg1447Met missense NM_001407944.1:c.4340G>T NP_001394873.1:p.Arg1447Met missense NM_001407945.1:c.4340G>T NP_001394874.1:p.Arg1447Met missense NM_001407946.1:c.4151G>T NP_001394875.1:p.Arg1384Met missense NM_001407947.1:c.4151G>T NP_001394876.1:p.Arg1384Met missense NM_001407948.1:c.4151G>T NP_001394877.1:p.Arg1384Met missense NM_001407949.1:c.4151G>T NP_001394878.1:p.Arg1384Met missense NM_001407950.1:c.4148G>T NP_001394879.1:p.Arg1383Met missense NM_001407951.1:c.4148G>T NP_001394880.1:p.Arg1383Met missense NM_001407952.1:c.4148G>T NP_001394881.1:p.Arg1383Met missense NM_001407953.1:c.4148G>T NP_001394882.1:p.Arg1383Met missense NM_001407954.1:c.4148G>T NP_001394883.1:p.Arg1383Met missense NM_001407955.1:c.4148G>T NP_001394884.1:p.Arg1383Met missense NM_001407956.1:c.4145G>T NP_001394885.1:p.Arg1382Met missense NM_001407957.1:c.4145G>T NP_001394886.1:p.Arg1382Met missense NM_001407958.1:c.4145G>T NP_001394887.1:p.Arg1382Met missense NM_001407959.1:c.4103G>T NP_001394888.1:p.Arg1368Met missense NM_001407960.1:c.4100G>T NP_001394889.1:p.Arg1367Met missense NM_001407962.1:c.4100G>T NP_001394891.1:p.Arg1367Met missense NM_001407963.1:c.4097G>T NP_001394892.1:p.Arg1366Met missense NM_001407965.1:c.3977G>T NP_001394894.1:p.Arg1326Met missense NM_001407966.1:c.3596G>T NP_001394895.1:p.Arg1199Met missense NM_001407967.1:c.3593G>T NP_001394896.1:p.Arg1198Met missense NM_001407968.1:c.1880G>T NP_001394897.1:p.Arg627Met missense NM_001407969.1:c.1877G>T NP_001394898.1:p.Arg626Met missense NM_001407970.1:c.1241G>T NP_001394899.1:p.Arg414Met missense NM_001407971.1:c.1241G>T NP_001394900.1:p.Arg414Met missense NM_001407972.1:c.1238G>T NP_001394901.1:p.Arg413Met missense NM_001407973.1:c.1175G>T NP_001394902.1:p.Arg392Met missense NM_001407974.1:c.1175G>T NP_001394903.1:p.Arg392Met missense NM_001407975.1:c.1175G>T NP_001394904.1:p.Arg392Met missense NM_001407976.1:c.1175G>T NP_001394905.1:p.Arg392Met missense NM_001407977.1:c.1175G>T NP_001394906.1:p.Arg392Met missense NM_001407978.1:c.1175G>T NP_001394907.1:p.Arg392Met missense NM_001407979.1:c.1172G>T NP_001394908.1:p.Arg391Met missense NM_001407980.1:c.1172G>T NP_001394909.1:p.Arg391Met missense NM_001407981.1:c.1172G>T NP_001394910.1:p.Arg391Met missense NM_001407982.1:c.1172G>T NP_001394911.1:p.Arg391Met missense NM_001407983.1:c.1172G>T NP_001394912.1:p.Arg391Met missense NM_001407984.1:c.1172G>T NP_001394913.1:p.Arg391Met missense NM_001407985.1:c.1172G>T NP_001394914.1:p.Arg391Met missense NM_001407986.1:c.1172G>T NP_001394915.1:p.Arg391Met missense NM_001407990.1:c.1172G>T NP_001394919.1:p.Arg391Met missense NM_001407991.1:c.1172G>T NP_001394920.1:p.Arg391Met missense NM_001407992.1:c.1172G>T NP_001394921.1:p.Arg391Met missense NM_001407993.1:c.1172G>T NP_001394922.1:p.Arg391Met missense NM_001408392.1:c.1169G>T NP_001395321.1:p.Arg390Met missense NM_001408396.1:c.1169G>T NP_001395325.1:p.Arg390Met missense NM_001408397.1:c.1169G>T NP_001395326.1:p.Arg390Met missense NM_001408398.1:c.1169G>T NP_001395327.1:p.Arg390Met missense NM_001408399.1:c.1169G>T NP_001395328.1:p.Arg390Met missense NM_001408400.1:c.1169G>T NP_001395329.1:p.Arg390Met missense NM_001408401.1:c.1169G>T NP_001395330.1:p.Arg390Met missense NM_001408402.1:c.1169G>T NP_001395331.1:p.Arg390Met missense NM_001408403.1:c.1169G>T NP_001395332.1:p.Arg390Met missense NM_001408404.1:c.1169G>T NP_001395333.1:p.Arg390Met missense NM_001408406.1:c.1166G>T NP_001395335.1:p.Arg389Met missense NM_001408407.1:c.1166G>T NP_001395336.1:p.Arg389Met missense NM_001408408.1:c.1166G>T NP_001395337.1:p.Arg389Met missense NM_001408409.1:c.1163G>T NP_001395338.1:p.Arg388Met missense NM_001408410.1:c.1100G>T NP_001395339.1:p.Arg367Met missense NM_001408411.1:c.1097G>T NP_001395340.1:p.Arg366Met missense NM_001408412.1:c.1094G>T NP_001395341.1:p.Arg365Met missense NM_001408413.1:c.1094G>T NP_001395342.1:p.Arg365Met missense NM_001408414.1:c.1094G>T NP_001395343.1:p.Arg365Met missense NM_001408415.1:c.1094G>T NP_001395344.1:p.Arg365Met missense NM_001408416.1:c.1094G>T NP_001395345.1:p.Arg365Met missense NM_001408418.1:c.1058G>T NP_001395347.1:p.Arg353Met missense NM_001408419.1:c.1058G>T NP_001395348.1:p.Arg353Met missense NM_001408420.1:c.1058G>T NP_001395349.1:p.Arg353Met missense NM_001408421.1:c.1055G>T NP_001395350.1:p.Arg352Met missense NM_001408422.1:c.1055G>T NP_001395351.1:p.Arg352Met missense NM_001408423.1:c.1055G>T NP_001395352.1:p.Arg352Met missense NM_001408424.1:c.1055G>T NP_001395353.1:p.Arg352Met missense NM_001408425.1:c.1052G>T NP_001395354.1:p.Arg351Met missense NM_001408426.1:c.1052G>T NP_001395355.1:p.Arg351Met missense NM_001408427.1:c.1052G>T NP_001395356.1:p.Arg351Met missense NM_001408428.1:c.1052G>T NP_001395357.1:p.Arg351Met missense NM_001408429.1:c.1052G>T NP_001395358.1:p.Arg351Met missense NM_001408430.1:c.1052G>T NP_001395359.1:p.Arg351Met missense NM_001408431.1:c.1052G>T NP_001395360.1:p.Arg351Met missense NM_001408432.1:c.1049G>T NP_001395361.1:p.Arg350Met missense NM_001408433.1:c.1049G>T NP_001395362.1:p.Arg350Met missense NM_001408434.1:c.1049G>T NP_001395363.1:p.Arg350Met missense NM_001408435.1:c.1049G>T NP_001395364.1:p.Arg350Met missense NM_001408436.1:c.1049G>T NP_001395365.1:p.Arg350Met missense NM_001408437.1:c.1049G>T NP_001395366.1:p.Arg350Met missense NM_001408438.1:c.1049G>T NP_001395367.1:p.Arg350Met missense NM_001408439.1:c.1049G>T NP_001395368.1:p.Arg350Met missense NM_001408440.1:c.1049G>T NP_001395369.1:p.Arg350Met missense NM_001408441.1:c.1049G>T NP_001395370.1:p.Arg350Met missense NM_001408442.1:c.1049G>T NP_001395371.1:p.Arg350Met missense NM_001408443.1:c.1049G>T NP_001395372.1:p.Arg350Met missense NM_001408444.1:c.1049G>T NP_001395373.1:p.Arg350Met missense NM_001408445.1:c.1046G>T NP_001395374.1:p.Arg349Met missense NM_001408446.1:c.1046G>T NP_001395375.1:p.Arg349Met missense NM_001408447.1:c.1046G>T NP_001395376.1:p.Arg349Met missense NM_001408448.1:c.1046G>T NP_001395377.1:p.Arg349Met missense NM_001408450.1:c.1046G>T NP_001395379.1:p.Arg349Met missense NM_001408451.1:c.1040G>T NP_001395380.1:p.Arg347Met missense NM_001408452.1:c.1034G>T NP_001395381.1:p.Arg345Met missense NM_001408453.1:c.1034G>T NP_001395382.1:p.Arg345Met missense NM_001408454.1:c.1034G>T NP_001395383.1:p.Arg345Met missense NM_001408455.1:c.1034G>T NP_001395384.1:p.Arg345Met missense NM_001408456.1:c.1034G>T NP_001395385.1:p.Arg345Met missense NM_001408457.1:c.1034G>T NP_001395386.1:p.Arg345Met missense NM_001408458.1:c.1031G>T NP_001395387.1:p.Arg344Met missense NM_001408459.1:c.1031G>T NP_001395388.1:p.Arg344Met missense NM_001408460.1:c.1031G>T NP_001395389.1:p.Arg344Met missense NM_001408461.1:c.1031G>T NP_001395390.1:p.Arg344Met missense NM_001408462.1:c.1031G>T NP_001395391.1:p.Arg344Met missense NM_001408463.1:c.1031G>T NP_001395392.1:p.Arg344Met missense NM_001408464.1:c.1031G>T NP_001395393.1:p.Arg344Met missense NM_001408465.1:c.1031G>T NP_001395394.1:p.Arg344Met missense NM_001408466.1:c.1031G>T NP_001395395.1:p.Arg344Met missense NM_001408467.1:c.1031G>T NP_001395396.1:p.Arg344Met missense NM_001408468.1:c.1028G>T NP_001395397.1:p.Arg343Met missense NM_001408469.1:c.1028G>T NP_001395398.1:p.Arg343Met missense NM_001408470.1:c.1028G>T NP_001395399.1:p.Arg343Met missense NM_001408472.1:c.1172G>T NP_001395401.1:p.Arg391Met missense NM_001408473.1:c.1169G>T NP_001395402.1:p.Arg390Met missense NM_001408474.1:c.974G>T NP_001395403.1:p.Arg325Met missense NM_001408475.1:c.971G>T NP_001395404.1:p.Arg324Met missense NM_001408476.1:c.971G>T NP_001395405.1:p.Arg324Met missense NM_001408478.1:c.965G>T NP_001395407.1:p.Arg322Met missense NM_001408479.1:c.965G>T NP_001395408.1:p.Arg322Met missense NM_001408480.1:c.965G>T NP_001395409.1:p.Arg322Met missense NM_001408481.1:c.962G>T NP_001395410.1:p.Arg321Met missense NM_001408482.1:c.962G>T NP_001395411.1:p.Arg321Met missense NM_001408483.1:c.962G>T NP_001395412.1:p.Arg321Met missense NM_001408484.1:c.962G>T NP_001395413.1:p.Arg321Met missense NM_001408485.1:c.962G>T NP_001395414.1:p.Arg321Met missense NM_001408489.1:c.962G>T NP_001395418.1:p.Arg321Met missense NM_001408490.1:c.962G>T NP_001395419.1:p.Arg321Met missense NM_001408491.1:c.962G>T NP_001395420.1:p.Arg321Met missense NM_001408492.1:c.959G>T NP_001395421.1:p.Arg320Met missense NM_001408493.1:c.959G>T NP_001395422.1:p.Arg320Met missense NM_001408494.1:c.935G>T NP_001395423.1:p.Arg312Met missense NM_001408495.1:c.929G>T NP_001395424.1:p.Arg310Met missense NM_001408496.1:c.911G>T NP_001395425.1:p.Arg304Met missense NM_001408497.1:c.911G>T NP_001395426.1:p.Arg304Met missense NM_001408498.1:c.911G>T NP_001395427.1:p.Arg304Met missense NM_001408499.1:c.911G>T NP_001395428.1:p.Arg304Met missense NM_001408500.1:c.911G>T NP_001395429.1:p.Arg304Met missense NM_001408501.1:c.911G>T NP_001395430.1:p.Arg304Met missense NM_001408502.1:c.908G>T NP_001395431.1:p.Arg303Met missense NM_001408503.1:c.908G>T NP_001395432.1:p.Arg303Met missense NM_001408504.1:c.908G>T NP_001395433.1:p.Arg303Met missense NM_001408505.1:c.905G>T NP_001395434.1:p.Arg302Met missense NM_001408506.1:c.848G>T NP_001395435.1:p.Arg283Met missense NM_001408507.1:c.845G>T NP_001395436.1:p.Arg282Met missense NM_001408508.1:c.836G>T NP_001395437.1:p.Arg279Met missense NM_001408509.1:c.833G>T NP_001395438.1:p.Arg278Met missense NM_001408510.1:c.794G>T NP_001395439.1:p.Arg265Met missense NM_001408511.1:c.791G>T NP_001395440.1:p.Arg264Met missense NM_001408512.1:c.671G>T NP_001395441.1:p.Arg224Met missense NM_007297.4:c.4343G>T NP_009228.2:p.Arg1448Met missense NM_007298.4:c.1172G>T NP_009229.2:p.Arg391Met missense NM_007299.4:c.1172G>T NP_009230.2:p.Arg391Met missense NM_007300.4:c.4547G>T NP_009231.2:p.Arg1516Met missense NM_007304.2:c.1172G>T NP_009235.2:p.Arg391Met missense NR_027676.2:n.4661G>T non-coding transcript variant NC_000017.11:g.43076488C>A NC_000017.10:g.41228505C>A NG_005905.2:g.141496G>T LRG_292:g.141496G>T LRG_292t1:c.4484G>T LRG_292p1:p.Arg1495Met P38398:p.Arg1495Met U14680.1:n.4603G>T - Protein change
- R1495M, R1516M, R1448M, R391M, R1198M, R1326M, R1368M, R1383M, R1384M, R1469M, R1491M, R1493M, R283M, R303M, R310M, R320M, R321M, R324M, R352M, R365M, R366M, R389M, R626M, R1406M, R1407M, R1423M, R1424M, R1454M, R1476M, R1515M, R224M, R279M, R325M, R343M, R344M, R347M, R353M, R367M, R392M, R414M, R1199M, R1382M, R1405M, R1425M, R1428M, R1447M, R1453M, R1468M, R1490M, R1494M, R282M, R302M, R304M, R322M, R350M, R388M, R390M, R627M, R1366M, R1367M, R1426M, R1446M, R1451M, R1452M, R1467M, R1475M, R1492M, R1517M, R264M, R265M, R278M, R312M, R345M, R349M, R351M, R413M
- Other names
-
p.R1495M:AGG>ATG
4603G>T
- Canonical SPDI
- NC_000017.11:43076487:C:A
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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. |
|---|---|---|---|---|
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2024 | RCV000031179.23 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 11, 2024 | RCV000048576.37 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2023 | RCV000131886.19 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 4, 2022 | RCV000159992.20 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2016 | RCV000238601.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 23, 2017 | RCV000462940.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 28, 2022 | RCV000770739.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 1, 2019 | RCV001171414.11 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000540946.1
First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 11, 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: SCV000076589.15
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 1495 of the BRCA1 protein (p.Arg1495Met). … (more)
This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 1495 of the BRCA1 protein (p.Arg1495Met). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80357389, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 10571952, 10923033, 22144684, 23096355, 24607278). It has also been observed to segregate with disease in related individuals. This variant is also known as 4603G>T and c.4547G>T. ClinVar contains an entry for this variant (Variation ID: 37598). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 13 and introduces a premature termination codon (PMID: 10571952, 12915465, 21120943, 24607278; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000605750.4
First in ClinVar: Aug 27, 2017 Last updated: Apr 20, 2024 |
Comment:
The p.Arg1495Met variant in BRCA1 has been reported in more than 30 individuals with hereditary breast and ovarian cancer (HBOC) and segregated with disease in … (more)
The p.Arg1495Met variant in BRCA1 has been reported in more than 30 individuals with hereditary breast and ovarian cancer (HBOC) and segregated with disease in at least 4 affected relatives from 2 families (Santos 2014 PMID: 24607278, Ripamonti 2013 PMID: 23374397, Breast Cancer Information Core (BIC) database). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 37598) and has been identified in 0.0009% (1/113592) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of HBOC in the general population. This variant is located in the last three bases of the exon, which is part of the 5’ splice region and several in vitro functional studies using patient RNA and minigene splicing assays have shown that the p.Arg1495Met causes skipping of exon 13 (Colombo 2013 PMID: 23451180, Santos 2014 PMID: 24607278, Houdayer 2012 PMID: 22505045), leading to resulting in a frameshift and resulting in a premature termination codon. In addition, additional variants involving this codon (p.Arg1495Thr and p.Arg1495Lys) have been identified in several individuals with HBOC and are classified as pathogenic in ClinVar by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) and several clinical laboratories, respectively. In summary, the p.Arg1495Met variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5, PP1, PS3_Moderate. (less)
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Pathogenic
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004215024.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Oct 30, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000223754.1
First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 |
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Pathogenic
(Jul 31, 2016)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699152.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The BRCA1 c.4484G>T (p.Arg1495Met) variant causes a missense change involving a conserved nucleotide, located at the most 3' position, i.e., the last nucleotide … (more)
Variant summary: The BRCA1 c.4484G>T (p.Arg1495Met) variant causes a missense change involving a conserved nucleotide, located at the most 3' position, i.e., the last nucleotide of exon 13. It is predicted to disrupt the natural splice donor site and cause abnormal splicing. 5/5 splicing prediction tools, predict alterations to splicing, consistent with the observed functional studies that implicate an affect on splicing. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 1/121358, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in multiple affected individuals via publications, along with multiple reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic. (less)
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Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001140523.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: research
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
Genetics Program, Instituto Nacional de Cancer
Accession: SCV002515213.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Geographic origin: Brazil
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Pathogenic
(Oct 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000325979.4
First in ClinVar: Jun 08, 2015 Last updated: Dec 11, 2022 |
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Pathogenic
(Jan 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000210177.15
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Published splicing studies demonstrate a damaging effect: Exonic splice resulting in out-of-frame skipping of exon 13, as well as minor amounts of transcript with in-frame … (more)
Published splicing studies demonstrate a damaging effect: Exonic splice resulting in out-of-frame skipping of exon 13, as well as minor amounts of transcript with in-frame skipping of exons 13-14 (also referred to as exons 14 and 15 in the literature) (Ozcelik 1999, Yang 2003, Houdayer 2012, Colombo 2013, Santos 2014); Observed in multiple individuals with personal and/or family histories of breast and ovarian cancer, segregating with cancer in at least one of these families (Aziz 2001, Caux-Moncoutier 2011, Zhang 2011, Lara 2012, Ripamonti 2013, Santos 2014, Pal 2015, Finch 2015, Pellegrino 2016, Brianese 2017); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4603G>T; This variant is associated with the following publications: (PMID: 25782689, 21324516, 27163896, 12915465, 26219728, 10571952, 21447777, 26913838, 23374397, 24607278, 26287763, 21120943, 25896959, 24916970, 18092194, 23096355, 17924331, 27914478, 27225819, 29116469, 28465148, 28475402, 28781887, 30283497, 29907814, 28423363, 31013702, 30606148, 30765603, 30159786, 22505045, 32885271, 29446198, 11263928, 33087888, 23451180, 32427313, 30787465, 21990134, 15343273, 22737296) (less)
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Pathogenic
(Dec 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296380.5
First in ClinVar: Oct 09, 2016 Last updated: Jan 06, 2024 |
Comment:
In the published literature, it has been reported in women affected with breast cancer (PMIDs: 18694767 (2008), 26287763 (2015)), ovarian cancer (PMIDs: 10571952 (1999), 27914478 … (more)
In the published literature, it has been reported in women affected with breast cancer (PMIDs: 18694767 (2008), 26287763 (2015)), ovarian cancer (PMIDs: 10571952 (1999), 27914478 (2016)), and fallopian tube cancer (PMID: 11263928 (2001)). Functional studies have shown that this variant causes skipping of BRCA1 exon 14 (PMIDs: 12915465 (2003), 22505045 (2012), 12915465 (2003)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000296803.1
First in ClinVar: Jul 31, 2016 Last updated: Jul 31, 2016 |
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Pathogenic
(Jul 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512513.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 strong, PS3, PS4 strong, PS4, PM2 moderate, PM2, PP1 moderate, PP3 supporting
Geographic origin: Brazil
|
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Pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537753.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA1 c.4484G>T (p.R1495M) variant has been reported in heterozygosity in numerous individuals with hereditary breast and/or ovarian cancer (PMID: 23096355, 18092194, 28423363, 24607278, 21120943, … (more)
The BRCA1 c.4484G>T (p.R1495M) variant has been reported in heterozygosity in numerous individuals with hereditary breast and/or ovarian cancer (PMID: 23096355, 18092194, 28423363, 24607278, 21120943, among others). This change occurs in the last base pair of exon 13. Experimental studies have shown that this variant results in aberrant splicing, leading to out-of-frame deletion of exon 13 (PMID: 23451180, 12915465, 24607278, 21120943). It is also known as c.4603G>T in the literature. This variant was observed in 1/113592 chromosomes in the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 37598). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000902222.2 First in ClinVar: May 06, 2019 Last updated: Mar 11, 2023 |
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Pathogenic
(Sep 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186941.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.4484G>T pathogenic mutation (also known as p.R1495M), located in coding exon 12 of the BRCA1 gene, results from a G to T substitution at … (more)
The c.4484G>T pathogenic mutation (also known as p.R1495M), located in coding exon 12 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4484. The amino acid change results in arginine to methionine at codon 1495, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. The c.4484G>T mutation has been reported in hereditary breast and ovarian cancer patients and multiple, independent splicing studies have demonstrated that it leads to exon skipping and predicted premature protein truncation (Ambry internal data; Ozcelik H et al. Hum Mutat, 1999;14:540-1; Aziz S et al. Gynecol. Oncol. 2001 Mar;80:341-5; Yang Y et al. Hum. Mol. Genet. 2003 Sep;12:2121-31; Tommasi S et al. Mutat. Res. 2008 Sep;644:64-70; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Lu W et al. Fam Cancer, 2012 Sep;11:381-5; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Lara K et al. Biol. Res. 2012;45:117-30; Ripamonti CB et al. BMC Cancer, 2013 Feb;13:46; Dodova RI et al. BMC Cancer, 2015 Jul;15:523; Maistro S et al. BMC Cancer. 2016 Dec;16:934; Palmero EI et al. Sci Rep, 2018 06;8:9188; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Marchetti C et al. Ann Surg Oncol, 2018 Nov;25:3701-3708; de Souza Timoteo AR et al. Breast Cancer Res Treat, 2018 Dec;172:637-646; Cotrim DP et al. BMC Cancer, 2019 Jan;19:4; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Artioli G et al. Gynecol Oncol, 2021 Jun;161:755-761). This mutation was also reported in a patient with endometrial cancer who also had family history of ovarian cancer (Vietri MT et al. Med Oncol, 2021 Jan;38:13). In addition, this alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). Of note, this alteration is also designated as 4603G>T in published literature. This nucleotide position is highly conserved in available vertebrate species. In addition, In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as a pathogenic mutation. (less)
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Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537652.4
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with methionine at codon 1495 and causes a G>T nucleotide substitution at the last nucleotide of exon 13 of the … (more)
This missense variant replaces arginine with methionine at codon 1495 and causes a G>T nucleotide substitution at the last nucleotide of exon 13 of the BRCA1 gene. Multiple RNA studies on carrier RNA and minigene splicing assay have consistently found that this variant causes the out-of-frame skipping of exon 13 resulting in a premature termination codon (PMID: 10571952, 12915465, 21120943, 22505045, 23451180, 24607278, 31843900). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 10571952, 18092194, 18159056, 18694767, 21120943, 21324516, 22476429, 23096355, 23374397, 24607278, 27914478, 28423363, 31843900). This variant has been reported with family history and co-segregation likelihood ratios for pathogenicity of 5.28 and 2.42, respectively (PMID: 17924331, 24607278). This variant has been identified in 1/251172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(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: SCV004817666.1
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)
|
Comment:
This missense variant replaces arginine with methionine at codon 1495 and causes a G>T nucleotide substitution at the last nucleotide of exon 13 of the … (more)
This missense variant replaces arginine with methionine at codon 1495 and causes a G>T nucleotide substitution at the last nucleotide of exon 13 of the BRCA1 gene. Multiple RNA studies on carrier RNA and minigene splicing assay have consistently found that this variant causes the out-of-frame skipping of exon 13 resulting in a premature termination codon (PMID: 10571952, 12915465, 21120943, 22505045, 23451180, 24607278, 31843900). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 10571952, 18092194, 18159056, 18694767, 21120943, 21324516, 22476429, 23096355, 23374397, 24607278, 27914478, 28423363, 31843900). This variant has been reported with family history and co-segregation likelihood ratios for pathogenicity of 5.28 and 2.42, respectively (PMID: 17924331, 24607278). This variant has been identified in 1/251172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 2
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Pathogenic
(May 01, 2012)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000053779.6
First in ClinVar: Apr 04, 2013 Last updated: Jun 08, 2015 |
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Pathogenic
(Jan 31, 2014)
|
no assertion criteria provided
Method: research
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587401.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
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|
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Pathogenic
(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: SCV000145100.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 10
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Venezuela
Observation 3:
Number of individuals with the variant: 1
Geographic origin: Western European
Observation 4:
Number of individuals with the variant: 2
Ethnicity/Population group: Caucasian
Geographic origin: Italy
Observation 5:
Number of individuals with the variant: 2
Ethnicity/Population group: Central/Eastern European
Observation 6:
Number of individuals with the variant: 1
Ethnicity/Population group: Italian
Observation 7:
Number of individuals with the variant: 1
Ethnicity/Population group: Latin American, Caribbean
Observation 8:
Number of individuals with the variant: 1
Ethnicity/Population group: Latin American, Caribbean, Grenadan
Observation 9:
Number of individuals with the variant: 4
Ethnicity/Population group: Western European
Observation 10:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Central/Eastern European, Scottish, Italian, Irish, Russian
Observation 11:
Number of individuals with the variant: 2
Ethnicity/Population group: Western European, Italian
Observation 12:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Italian, Irish
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Pathogenic
(Sep 01, 2019)
|
no assertion criteria provided
Method: research
|
Hereditary breast and ovarian cancer syndrome
Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
|
King Laboratory, University of Washington
Accession: SCV001251319.1
First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020
Comment:
Transcript analysis by cBROCA
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|
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Pathogenic
(Aug 26, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
BRCAlab, Lund University
Accession: SCV002588812.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
|
|
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Pathogenic
(-)
|
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: SCV000591519.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The BRCA1 p.Arg1495Met variant was identified in 7 of 8214 proband chromosomes (frequency: 0.0009) from individuals or families with breast and/or ovarian cancer or fallopian … (more)
The BRCA1 p.Arg1495Met variant was identified in 7 of 8214 proband chromosomes (frequency: 0.0009) from individuals or families with breast and/or ovarian cancer or fallopian tube cancer (Zhang 2011, Shattuck-Eidens 1997, Nedelcu 2002, Aziz 2001, John 2007, Pilato 2010). The variant was also identified in the following databases: dbSNP (ID: rs80357389) as “With Pathogenic allele”, ClinVar and Clinvitae (12x - classified as pathogenic by Ambry Genetics, GeneDx, Pathway Genomics, Quest Diagnostics, GeneKor, Univ. of Cambridge, Color Genomics, Baylor Miraca Genetics, Invitae, BIC, SCRP, COGR), COGR (2x - classified as pathogenic by Sinai Health System and COGR consensus), LOVD 3.0 (3x classified as affects function), UMD-LSDB (12x classified as causal), BIC Database (27 submissions, classification pending), and the ARUP Laboratories (classified as definitely pathogenic). The variant was not identified in COSMIC, MutDB, or Zhejiang Colon Cancer databases. The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 1 of 245958 chromosomes at a frequency of 0.000004 (one individual of European non-Finnish ethnicity; freq. 0.000009) (Genome Aggregation Consortium Feb 27, 2017). This variant was observed by RT-PCR to result increased levels of alternative transcripts demonstrating both an out-of-frame deletion of exon 14 as well as an in-frame deletion of exons 14 and 15 (Santos 2014). Together with co-segregation data the authors conclude that this variant is considered pathogenic. A humanized mouse model system demonstrated that this variant causes aberrant splicing resulting in the deletion of exon 14 due to possible disruption of cis-acting splicing regulatory elements (Yang 2003). The p.Arg1495Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Arg1495Met variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Comment:
Comment:
The p.Arg1495Met variant in BRCA1 has been reported in more than 30 individuals with hereditary breast and ovarian cancer (HBOC) and segregated with disease in at least 4 affected relatives from 2 families (Santos 2014 PMID: 24607278, Ripamonti 2013 PMID: 23374397, Breast Cancer Information Core (BIC) database). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 37598) and has been identified in 0.0009% (1/113592) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of HBOC in the general population. This variant is located in the last three bases of the exon, which is part of the 5’ splice region and several in vitro functional studies using patient RNA and minigene splicing assays have shown that the p.Arg1495Met causes skipping of exon 13 (Colombo 2013 PMID: 23451180, Santos 2014 PMID: 24607278, Houdayer 2012 PMID: 22505045), leading to resulting in a frameshift and resulting in a premature termination codon. In addition, additional variants involving this codon (p.Arg1495Thr and p.Arg1495Lys) have been identified in several individuals with HBOC and are classified as pathogenic in ClinVar by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) and several clinical laboratories, respectively. In summary, the p.Arg1495Met variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5, PP1, PS3_Moderate.
Comment:
Variant summary: The BRCA1 c.4484G>T (p.Arg1495Met) variant causes a missense change involving a conserved nucleotide, located at the most 3' position, i.e., the last nucleotide of exon 13. It is predicted to disrupt the natural splice donor site and cause abnormal splicing. 5/5 splicing prediction tools, predict alterations to splicing, consistent with the observed functional studies that implicate an affect on splicing. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 1/121358, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in multiple affected individuals via publications, along with multiple reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic.
Comment:
Published splicing studies demonstrate a damaging effect: Exonic splice resulting in out-of-frame skipping of exon 13, as well as minor amounts of transcript with in-frame skipping of exons 13-14 (also referred to as exons 14 and 15 in the literature) (Ozcelik 1999, Yang 2003, Houdayer 2012, Colombo 2013, Santos 2014); Observed in multiple individuals with personal and/or family histories of breast and ovarian cancer, segregating with cancer in at least one of these families (Aziz 2001, Caux-Moncoutier 2011, Zhang 2011, Lara 2012, Ripamonti 2013, Santos 2014, Pal 2015, Finch 2015, Pellegrino 2016, Brianese 2017); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4603G>T; This variant is associated with the following publications: (PMID: 25782689, 21324516, 27163896, 12915465, 26219728, 10571952, 21447777, 26913838, 23374397, 24607278, 26287763, 21120943, 25896959, 24916970, 18092194, 23096355, 17924331, 27914478, 27225819, 29116469, 28465148, 28475402, 28781887, 30283497, 29907814, 28423363, 31013702, 30606148, 30765603, 30159786, 22505045, 32885271, 29446198, 11263928, 33087888, 23451180, 32427313, 30787465, 21990134, 15343273, 22737296)
Comment:
In the published literature, it has been reported in women affected with breast cancer (PMIDs: 18694767 (2008), 26287763 (2015)), ovarian cancer (PMIDs: 10571952 (1999), 27914478 (2016)), and fallopian tube cancer (PMID: 11263928 (2001)). Functional studies have shown that this variant causes skipping of BRCA1 exon 14 (PMIDs: 12915465 (2003), 22505045 (2012), 12915465 (2003)). Based on the available information, this variant is classified as pathogenic.
Comment:
ACMG classification criteria: PS3 strong, PS3, PS4 strong, PS4, PM2 moderate, PM2, PP1 moderate, PP3 supporting
Comment:
The c.4484G>T pathogenic mutation (also known as p.R1495M), located in coding exon 12 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4484. The amino acid change results in arginine to methionine at codon 1495, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. The c.4484G>T mutation has been reported in hereditary breast and ovarian cancer patients and multiple, independent splicing studies have demonstrated that it leads to exon skipping and predicted premature protein truncation (Ambry internal data; Ozcelik H et al. Hum Mutat, 1999;14:540-1; Aziz S et al. Gynecol. Oncol. 2001 Mar;80:341-5; Yang Y et al. Hum. Mol. Genet. 2003 Sep;12:2121-31; Tommasi S et al. Mutat. Res. 2008 Sep;644:64-70; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Lu W et al. Fam Cancer, 2012 Sep;11:381-5; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Lara K et al. Biol. Res. 2012;45:117-30; Ripamonti CB et al. BMC Cancer, 2013 Feb;13:46; Dodova RI et al. BMC Cancer, 2015 Jul;15:523; Maistro S et al. BMC Cancer. 2016 Dec;16:934; Palmero EI et al. Sci Rep, 2018 06;8:9188; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Marchetti C et al. Ann Surg Oncol, 2018 Nov;25:3701-3708; de Souza Timoteo AR et al. Breast Cancer Res Treat, 2018 Dec;172:637-646; Cotrim DP et al. BMC Cancer, 2019 Jan;19:4; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Artioli G et al. Gynecol Oncol, 2021 Jun;161:755-761). This mutation was also reported in a patient with endometrial cancer who also had family history of ovarian cancer (Vietri MT et al. Med Oncol, 2021 Jan;38:13). In addition, this alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). Of note, this alteration is also designated as 4603G>T in published literature. This nucleotide position is highly conserved in available vertebrate species. In addition, In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as a pathogenic mutation.
Comment:
This missense variant replaces arginine with methionine at codon 1495 and causes a G>T nucleotide substitution at the last nucleotide of exon 13 of the BRCA1 gene. Multiple RNA studies on carrier RNA and minigene splicing assay have consistently found that this variant causes the out-of-frame skipping of exon 13 resulting in a premature termination codon (PMID: 10571952, 12915465, 21120943, 22505045, 23451180, 24607278, 31843900). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 10571952, 18092194, 18159056, 18694767, 21120943, 21324516, 22476429, 23096355, 23374397, 24607278, 27914478, 28423363, 31843900). This variant has been reported with family history and co-segregation likelihood ratios for pathogenicity of 5.28 and 2.42, respectively (PMID: 17924331, 24607278). This variant has been identified in 1/251172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This missense variant replaces arginine with methionine at codon 1495 and causes a G>T nucleotide substitution at the last nucleotide of exon 13 of the BRCA1 gene. Multiple RNA studies on carrier RNA and minigene splicing assay have consistently found that this variant causes the out-of-frame skipping of exon 13 resulting in a premature termination codon (PMID: 10571952, 12915465, 21120943, 22505045, 23451180, 24607278, 31843900). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 10571952, 18092194, 18159056, 18694767, 21120943, 21324516, 22476429, 23096355, 23374397, 24607278, 27914478, 28423363, 31843900). This variant has been reported with family history and co-segregation likelihood ratios for pathogenicity of 5.28 and 2.42, respectively (PMID: 17924331, 24607278). This variant has been identified in 1/251172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The BRCA1 p.Arg1495Met variant was identified in 7 of 8214 proband chromosomes (frequency: 0.0009) from individuals or families with breast and/or ovarian cancer or fallopian tube cancer (Zhang 2011, Shattuck-Eidens 1997, Nedelcu 2002, Aziz 2001, John 2007, Pilato 2010). The variant was also identified in the following databases: dbSNP (ID: rs80357389) as “With Pathogenic allele”, ClinVar and Clinvitae (12x - classified as pathogenic by Ambry Genetics, GeneDx, Pathway Genomics, Quest Diagnostics, GeneKor, Univ. of Cambridge, Color Genomics, Baylor Miraca Genetics, Invitae, BIC, SCRP, COGR), COGR (2x - classified as pathogenic by Sinai Health System and COGR consensus), LOVD 3.0 (3x classified as affects function), UMD-LSDB (12x classified as causal), BIC Database (27 submissions, classification pending), and the ARUP Laboratories (classified as definitely pathogenic). The variant was not identified in COSMIC, MutDB, or Zhejiang Colon Cancer databases. The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 1 of 245958 chromosomes at a frequency of 0.000004 (one individual of European non-Finnish ethnicity; freq. 0.000009) (Genome Aggregation Consortium Feb 27, 2017). This variant was observed by RT-PCR to result increased levels of alternative transcripts demonstrating both an out-of-frame deletion of exon 14 as well as an in-frame deletion of exons 14 and 15 (Santos 2014). Together with co-segregation data the authors conclude that this variant is considered pathogenic. A humanized mouse model system demonstrated that this variant causes aberrant splicing resulting in the deletion of exon 14 due to possible disruption of cis-acting splicing regulatory elements (Yang 2003). The p.Arg1495Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Arg1495Met variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
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 sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 1495 of the BRCA1 protein (p.Arg1495Met). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80357389, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 10571952, 10923033, 22144684, 23096355, 24607278). It has also been observed to segregate with disease in related individuals. This variant is also known as 4603G>T and c.4547G>T. ClinVar contains an entry for this variant (Variation ID: 37598). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 13 and introduces a premature termination codon (PMID: 10571952, 12915465, 21120943, 24607278; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Arg1495Met variant in BRCA1 has been reported in more than 30 individuals with hereditary breast and ovarian cancer (HBOC) and segregated with disease in at least 4 affected relatives from 2 families (Santos 2014 PMID: 24607278, Ripamonti 2013 PMID: 23374397, Breast Cancer Information Core (BIC) database). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 37598) and has been identified in 0.0009% (1/113592) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of HBOC in the general population. This variant is located in the last three bases of the exon, which is part of the 5’ splice region and several in vitro functional studies using patient RNA and minigene splicing assays have shown that the p.Arg1495Met causes skipping of exon 13 (Colombo 2013 PMID: 23451180, Santos 2014 PMID: 24607278, Houdayer 2012 PMID: 22505045), leading to resulting in a frameshift and resulting in a premature termination codon. In addition, additional variants involving this codon (p.Arg1495Thr and p.Arg1495Lys) have been identified in several individuals with HBOC and are classified as pathogenic in ClinVar by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) and several clinical laboratories, respectively. In summary, the p.Arg1495Met variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5, PP1, PS3_Moderate.
Comment:
Variant summary: The BRCA1 c.4484G>T (p.Arg1495Met) variant causes a missense change involving a conserved nucleotide, located at the most 3' position, i.e., the last nucleotide of exon 13. It is predicted to disrupt the natural splice donor site and cause abnormal splicing. 5/5 splicing prediction tools, predict alterations to splicing, consistent with the observed functional studies that implicate an affect on splicing. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 1/121358, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in multiple affected individuals via publications, along with multiple reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic.
Comment:
Published splicing studies demonstrate a damaging effect: Exonic splice resulting in out-of-frame skipping of exon 13, as well as minor amounts of transcript with in-frame skipping of exons 13-14 (also referred to as exons 14 and 15 in the literature) (Ozcelik 1999, Yang 2003, Houdayer 2012, Colombo 2013, Santos 2014); Observed in multiple individuals with personal and/or family histories of breast and ovarian cancer, segregating with cancer in at least one of these families (Aziz 2001, Caux-Moncoutier 2011, Zhang 2011, Lara 2012, Ripamonti 2013, Santos 2014, Pal 2015, Finch 2015, Pellegrino 2016, Brianese 2017); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4603G>T; This variant is associated with the following publications: (PMID: 25782689, 21324516, 27163896, 12915465, 26219728, 10571952, 21447777, 26913838, 23374397, 24607278, 26287763, 21120943, 25896959, 24916970, 18092194, 23096355, 17924331, 27914478, 27225819, 29116469, 28465148, 28475402, 28781887, 30283497, 29907814, 28423363, 31013702, 30606148, 30765603, 30159786, 22505045, 32885271, 29446198, 11263928, 33087888, 23451180, 32427313, 30787465, 21990134, 15343273, 22737296)
Comment:
In the published literature, it has been reported in women affected with breast cancer (PMIDs: 18694767 (2008), 26287763 (2015)), ovarian cancer (PMIDs: 10571952 (1999), 27914478 (2016)), and fallopian tube cancer (PMID: 11263928 (2001)). Functional studies have shown that this variant causes skipping of BRCA1 exon 14 (PMIDs: 12915465 (2003), 22505045 (2012), 12915465 (2003)). Based on the available information, this variant is classified as pathogenic.
Comment:
ACMG classification criteria: PS3 strong, PS3, PS4 strong, PS4, PM2 moderate, PM2, PP1 moderate, PP3 supporting
Comment:
The c.4484G>T pathogenic mutation (also known as p.R1495M), located in coding exon 12 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4484. The amino acid change results in arginine to methionine at codon 1495, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. The c.4484G>T mutation has been reported in hereditary breast and ovarian cancer patients and multiple, independent splicing studies have demonstrated that it leads to exon skipping and predicted premature protein truncation (Ambry internal data; Ozcelik H et al. Hum Mutat, 1999;14:540-1; Aziz S et al. Gynecol. Oncol. 2001 Mar;80:341-5; Yang Y et al. Hum. Mol. Genet. 2003 Sep;12:2121-31; Tommasi S et al. Mutat. Res. 2008 Sep;644:64-70; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Lu W et al. Fam Cancer, 2012 Sep;11:381-5; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Lara K et al. Biol. Res. 2012;45:117-30; Ripamonti CB et al. BMC Cancer, 2013 Feb;13:46; Dodova RI et al. BMC Cancer, 2015 Jul;15:523; Maistro S et al. BMC Cancer. 2016 Dec;16:934; Palmero EI et al. Sci Rep, 2018 06;8:9188; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Marchetti C et al. Ann Surg Oncol, 2018 Nov;25:3701-3708; de Souza Timoteo AR et al. Breast Cancer Res Treat, 2018 Dec;172:637-646; Cotrim DP et al. BMC Cancer, 2019 Jan;19:4; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Artioli G et al. Gynecol Oncol, 2021 Jun;161:755-761). This mutation was also reported in a patient with endometrial cancer who also had family history of ovarian cancer (Vietri MT et al. Med Oncol, 2021 Jan;38:13). In addition, this alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). Of note, this alteration is also designated as 4603G>T in published literature. This nucleotide position is highly conserved in available vertebrate species. In addition, In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as a pathogenic mutation.
Comment:
This missense variant replaces arginine with methionine at codon 1495 and causes a G>T nucleotide substitution at the last nucleotide of exon 13 of the BRCA1 gene. Multiple RNA studies on carrier RNA and minigene splicing assay have consistently found that this variant causes the out-of-frame skipping of exon 13 resulting in a premature termination codon (PMID: 10571952, 12915465, 21120943, 22505045, 23451180, 24607278, 31843900). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 10571952, 18092194, 18159056, 18694767, 21120943, 21324516, 22476429, 23096355, 23374397, 24607278, 27914478, 28423363, 31843900). This variant has been reported with family history and co-segregation likelihood ratios for pathogenicity of 5.28 and 2.42, respectively (PMID: 17924331, 24607278). This variant has been identified in 1/251172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This missense variant replaces arginine with methionine at codon 1495 and causes a G>T nucleotide substitution at the last nucleotide of exon 13 of the BRCA1 gene. Multiple RNA studies on carrier RNA and minigene splicing assay have consistently found that this variant causes the out-of-frame skipping of exon 13 resulting in a premature termination codon (PMID: 10571952, 12915465, 21120943, 22505045, 23451180, 24607278, 31843900). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 10571952, 18092194, 18159056, 18694767, 21120943, 21324516, 22476429, 23096355, 23374397, 24607278, 27914478, 28423363, 31843900). This variant has been reported with family history and co-segregation likelihood ratios for pathogenicity of 5.28 and 2.42, respectively (PMID: 17924331, 24607278). This variant has been identified in 1/251172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The BRCA1 p.Arg1495Met variant was identified in 7 of 8214 proband chromosomes (frequency: 0.0009) from individuals or families with breast and/or ovarian cancer or fallopian tube cancer (Zhang 2011, Shattuck-Eidens 1997, Nedelcu 2002, Aziz 2001, John 2007, Pilato 2010). The variant was also identified in the following databases: dbSNP (ID: rs80357389) as “With Pathogenic allele”, ClinVar and Clinvitae (12x - classified as pathogenic by Ambry Genetics, GeneDx, Pathway Genomics, Quest Diagnostics, GeneKor, Univ. of Cambridge, Color Genomics, Baylor Miraca Genetics, Invitae, BIC, SCRP, COGR), COGR (2x - classified as pathogenic by Sinai Health System and COGR consensus), LOVD 3.0 (3x classified as affects function), UMD-LSDB (12x classified as causal), BIC Database (27 submissions, classification pending), and the ARUP Laboratories (classified as definitely pathogenic). The variant was not identified in COSMIC, MutDB, or Zhejiang Colon Cancer databases. The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 1 of 245958 chromosomes at a frequency of 0.000004 (one individual of European non-Finnish ethnicity; freq. 0.000009) (Genome Aggregation Consortium Feb 27, 2017). This variant was observed by RT-PCR to result increased levels of alternative transcripts demonstrating both an out-of-frame deletion of exon 14 as well as an in-frame deletion of exons 14 and 15 (Santos 2014). Together with co-segregation data the authors conclude that this variant is considered pathogenic. A humanized mouse model system demonstrated that this variant causes aberrant splicing resulting in the deletion of exon 14 due to possible disruption of cis-acting splicing regulatory elements (Yang 2003). The p.Arg1495Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Arg1495Met variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service. | Matta BP | Scientific reports | 2022 | PMID: 36329109 |
| Characteristics and outcome of BRCA mutated epithelial ovarian cancer patients in Italy: A retrospective multicenter study (MITO 21). | Artioli G | Gynecologic oncology | 2021 | PMID: 33888336 |
| Prevalence of mutations in BRCA and MMR genes in patients affected with hereditary endometrial cancer. | Vietri MT | Medical oncology (Northwood, London, England) | 2021 | PMID: 33484353 |
| Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
| Characterization of splice-altering mutations in inherited predisposition to cancer. | Casadei S | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 31843900 |
| Germline Missense Variants in BRCA1: New Trends and Challenges for Clinical Annotation. | Golubeva VA | Cancers | 2019 | PMID: 31013702 |
| Prevalence of BRCA1 and BRCA2 pathogenic and likely pathogenic variants in non-selected ovarian carcinoma patients in Brazil. | Cotrim DP | BMC cancer | 2019 | PMID: 30606148 |
| A portrait of germline mutation in Brazilian at-risk for hereditary breast cancer. | de Souza Timoteo AR | Breast cancer research and treatment | 2018 | PMID: 30159786 |
| BRCA Mutation Status to Personalize Management of Recurrent Ovarian Cancer: A Multicenter Study. | Marchetti C | Annals of surgical oncology | 2018 | PMID: 30128899 |
| The germline mutational landscape of BRCA1 and BRCA2 in Brazil. | Palmero EI | Scientific reports | 2018 | PMID: 29907814 |
| Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
| Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer. | Tedaldi G | Oncotarget | 2017 | PMID: 28423363 |
| Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. | Woods NT | NPJ genomic medicine | 2016 | PMID: 28781887 |
| Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil. | Maistro S | BMC cancer | 2016 | PMID: 27914478 |
| A high frequency of BRCA mutations in young black women with breast cancer residing in Florida. | Pal T | Cancer | 2015 | PMID: 26287763 |
| Spectrum and frequencies of BRCA1/2 mutations in Bulgarian high risk breast cancer patients. | Dodova RI | BMC cancer | 2015 | PMID: 26183948 |
| The molecular analysis of BRCA1 and BRCA2: Next-generation sequencing supersedes conventional approaches. | D'Argenio V | Clinica chimica acta; international journal of clinical chemistry | 2015 | PMID: 25896959 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| Pathogenicity evaluation of BRCA1 and BRCA2 unclassified variants identified in Portuguese breast/ovarian cancer families. | Santos C | The Journal of molecular diagnostics : JMD | 2014 | PMID: 24607278 |
| Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. | Colombo M | PloS one | 2013 | PMID: 23451180 |
| First description of an acinic cell carcinoma of the breast in a BRCA1 mutation carrier: a case report. | Ripamonti CB | BMC cancer | 2013 | PMID: 23374397 |
| BRCA1 and BRCA2 mutations in breast cancer patients from Venezuela. | Lara K | Biological research | 2012 | PMID: 23096355 |
| Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. | Houdayer C | Human mutation | 2012 | PMID: 22505045 |
| Mutation screening of RAD51C in high-risk breast and ovarian cancer families. | Lu W | Familial cancer | 2012 | PMID: 22476429 |
| Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. | Caputo S | Nucleic acids research | 2012 | PMID: 22144684 |
| A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). | Lindor NM | Human mutation | 2012 | PMID: 21990134 |
| A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1. | Iversen ES Jr | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2011 | PMID: 21447777 |
| Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. | Zhang S | Gynecologic oncology | 2011 | PMID: 21324516 |
| EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. | Caux-Moncoutier V | Human mutation | 2011 | PMID: 21120943 |
| Molecular and in silico analysis of BRCA1 and BRCA2 variants. | Tommasi S | Mutation research | 2008 | PMID: 18694767 |
| Results of a population-based screening for hereditary breast cancer in a region of North-Central Italy: contribution of BRCA1/2 germ-line mutations. | Seymour IJ | Breast cancer research and treatment | 2008 | PMID: 18092194 |
| Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. | John EM | JAMA | 2007 | PMID: 18159056 |
| A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. | Easton DF | American journal of human genetics | 2007 | PMID: 17924331 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Aberrant splicing induced by missense mutations in BRCA1: clues from a humanized mouse model. | Yang Y | Human molecular genetics | 2003 | PMID: 12915465 |
| A genetic epidemiological study of carcinoma of the fallopian tube. | Aziz S | Gynecologic oncology | 2001 | PMID: 11263928 |
| The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
| Mutation in the coding region of the BRCA1 gene leads to aberrant splicing of the transcript. | Ozcelik H | Human mutation | 1999 | PMID: 10571952 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs80357389 ...
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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.