Variant summary: BRCA1 c.2060A>C (p.Gln687Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251304 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2060A>C has been reported in the literature as a VUS in a setting of BRCA1/2 gene panel testing at least one case of ovarian cancer, however whether the variant was germline or somatic was not determined (e.g. Ellison_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). A companion study, (Cline_2019) was also in agreement with this classification. However, to our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16518693, 31294896, 25859162, 20167696, 31112341, 15385441, 23704879). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=4; likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.2060A>C (p.Gln687Pro)
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.
(11)
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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(7); Likely benign(2)
Uncertain significance(7); Likely benign(2)
11
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.2060A>C (p.Gln687Pro)
Variation ID: 37443 Accession: VCV000037443.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43093471 (GRCh38) [ NCBI UCSC ] 17: 41245488 (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 May 1, 2024 Jan 3, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.2060A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Gln687Pro missense NM_001407571.1:c.1847A>C NP_001394500.1:p.Gln616Pro missense NM_001407581.1:c.2060A>C NP_001394510.1:p.Gln687Pro missense NM_001407582.1:c.2060A>C NP_001394511.1:p.Gln687Pro missense NM_001407583.1:c.2060A>C NP_001394512.1:p.Gln687Pro missense NM_001407585.1:c.2060A>C NP_001394514.1:p.Gln687Pro missense NM_001407587.1:c.2057A>C NP_001394516.1:p.Gln686Pro missense NM_001407590.1:c.2057A>C NP_001394519.1:p.Gln686Pro missense NM_001407591.1:c.2057A>C NP_001394520.1:p.Gln686Pro missense NM_001407593.1:c.2060A>C NP_001394522.1:p.Gln687Pro missense NM_001407594.1:c.2060A>C NP_001394523.1:p.Gln687Pro missense NM_001407596.1:c.2060A>C NP_001394525.1:p.Gln687Pro missense NM_001407597.1:c.2060A>C NP_001394526.1:p.Gln687Pro missense NM_001407598.1:c.2060A>C NP_001394527.1:p.Gln687Pro missense NM_001407602.1:c.2060A>C NP_001394531.1:p.Gln687Pro missense NM_001407603.1:c.2060A>C NP_001394532.1:p.Gln687Pro missense NM_001407605.1:c.2060A>C NP_001394534.1:p.Gln687Pro missense NM_001407610.1:c.2057A>C NP_001394539.1:p.Gln686Pro missense NM_001407611.1:c.2057A>C NP_001394540.1:p.Gln686Pro missense NM_001407612.1:c.2057A>C NP_001394541.1:p.Gln686Pro missense NM_001407613.1:c.2057A>C NP_001394542.1:p.Gln686Pro missense NM_001407614.1:c.2057A>C NP_001394543.1:p.Gln686Pro missense NM_001407615.1:c.2057A>C NP_001394544.1:p.Gln686Pro missense NM_001407616.1:c.2060A>C NP_001394545.1:p.Gln687Pro missense NM_001407617.1:c.2060A>C NP_001394546.1:p.Gln687Pro missense NM_001407618.1:c.2060A>C NP_001394547.1:p.Gln687Pro missense NM_001407619.1:c.2060A>C NP_001394548.1:p.Gln687Pro missense NM_001407620.1:c.2060A>C NP_001394549.1:p.Gln687Pro missense NM_001407621.1:c.2060A>C NP_001394550.1:p.Gln687Pro missense NM_001407622.1:c.2060A>C NP_001394551.1:p.Gln687Pro missense NM_001407623.1:c.2060A>C NP_001394552.1:p.Gln687Pro missense NM_001407624.1:c.2060A>C NP_001394553.1:p.Gln687Pro missense NM_001407625.1:c.2060A>C NP_001394554.1:p.Gln687Pro missense NM_001407626.1:c.2060A>C NP_001394555.1:p.Gln687Pro missense NM_001407627.1:c.2057A>C NP_001394556.1:p.Gln686Pro missense NM_001407628.1:c.2057A>C NP_001394557.1:p.Gln686Pro missense NM_001407629.1:c.2057A>C NP_001394558.1:p.Gln686Pro missense NM_001407630.1:c.2057A>C NP_001394559.1:p.Gln686Pro missense NM_001407631.1:c.2057A>C NP_001394560.1:p.Gln686Pro missense NM_001407632.1:c.2057A>C NP_001394561.1:p.Gln686Pro missense NM_001407633.1:c.2057A>C NP_001394562.1:p.Gln686Pro missense NM_001407634.1:c.2057A>C NP_001394563.1:p.Gln686Pro missense NM_001407635.1:c.2057A>C NP_001394564.1:p.Gln686Pro missense NM_001407636.1:c.2057A>C NP_001394565.1:p.Gln686Pro missense NM_001407637.1:c.2057A>C NP_001394566.1:p.Gln686Pro missense NM_001407638.1:c.2057A>C NP_001394567.1:p.Gln686Pro missense NM_001407639.1:c.2060A>C NP_001394568.1:p.Gln687Pro missense NM_001407640.1:c.2060A>C NP_001394569.1:p.Gln687Pro missense NM_001407641.1:c.2060A>C NP_001394570.1:p.Gln687Pro missense NM_001407642.1:c.2060A>C NP_001394571.1:p.Gln687Pro missense NM_001407644.1:c.2057A>C NP_001394573.1:p.Gln686Pro missense NM_001407645.1:c.2057A>C NP_001394574.1:p.Gln686Pro missense NM_001407646.1:c.2051A>C NP_001394575.1:p.Gln684Pro missense NM_001407647.1:c.2051A>C NP_001394576.1:p.Gln684Pro missense NM_001407648.1:c.1937A>C NP_001394577.1:p.Gln646Pro missense NM_001407649.1:c.1934A>C NP_001394578.1:p.Gln645Pro missense NM_001407652.1:c.2060A>C NP_001394581.1:p.Gln687Pro missense NM_001407653.1:c.1982A>C NP_001394582.1:p.Gln661Pro missense NM_001407654.1:c.1982A>C NP_001394583.1:p.Gln661Pro missense NM_001407655.1:c.1982A>C NP_001394584.1:p.Gln661Pro missense NM_001407656.1:c.1982A>C NP_001394585.1:p.Gln661Pro missense NM_001407657.1:c.1982A>C NP_001394586.1:p.Gln661Pro missense NM_001407658.1:c.1982A>C NP_001394587.1:p.Gln661Pro missense NM_001407659.1:c.1979A>C NP_001394588.1:p.Gln660Pro missense NM_001407660.1:c.1979A>C NP_001394589.1:p.Gln660Pro missense NM_001407661.1:c.1979A>C NP_001394590.1:p.Gln660Pro missense NM_001407662.1:c.1979A>C NP_001394591.1:p.Gln660Pro missense NM_001407663.1:c.1982A>C NP_001394592.1:p.Gln661Pro missense NM_001407664.1:c.1937A>C NP_001394593.1:p.Gln646Pro missense NM_001407665.1:c.1937A>C NP_001394594.1:p.Gln646Pro missense NM_001407666.1:c.1937A>C NP_001394595.1:p.Gln646Pro missense NM_001407667.1:c.1937A>C NP_001394596.1:p.Gln646Pro missense NM_001407668.1:c.1937A>C NP_001394597.1:p.Gln646Pro missense NM_001407669.1:c.1937A>C NP_001394598.1:p.Gln646Pro missense NM_001407670.1:c.1934A>C NP_001394599.1:p.Gln645Pro missense NM_001407671.1:c.1934A>C NP_001394600.1:p.Gln645Pro missense NM_001407672.1:c.1934A>C NP_001394601.1:p.Gln645Pro missense NM_001407673.1:c.1934A>C NP_001394602.1:p.Gln645Pro missense NM_001407674.1:c.1937A>C NP_001394603.1:p.Gln646Pro missense NM_001407675.1:c.1937A>C NP_001394604.1:p.Gln646Pro missense NM_001407676.1:c.1937A>C NP_001394605.1:p.Gln646Pro missense NM_001407677.1:c.1937A>C NP_001394606.1:p.Gln646Pro missense NM_001407678.1:c.1937A>C NP_001394607.1:p.Gln646Pro missense NM_001407679.1:c.1937A>C NP_001394608.1:p.Gln646Pro missense NM_001407680.1:c.1937A>C NP_001394609.1:p.Gln646Pro missense NM_001407681.1:c.1937A>C NP_001394610.1:p.Gln646Pro missense NM_001407682.1:c.1937A>C NP_001394611.1:p.Gln646Pro missense NM_001407683.1:c.1937A>C NP_001394612.1:p.Gln646Pro missense NM_001407684.1:c.2060A>C NP_001394613.1:p.Gln687Pro missense NM_001407685.1:c.1934A>C NP_001394614.1:p.Gln645Pro missense NM_001407686.1:c.1934A>C NP_001394615.1:p.Gln645Pro missense NM_001407687.1:c.1934A>C NP_001394616.1:p.Gln645Pro missense NM_001407688.1:c.1934A>C NP_001394617.1:p.Gln645Pro missense NM_001407689.1:c.1934A>C NP_001394618.1:p.Gln645Pro missense NM_001407690.1:c.1934A>C NP_001394619.1:p.Gln645Pro missense NM_001407691.1:c.1934A>C NP_001394620.1:p.Gln645Pro missense NM_001407692.1:c.1919A>C NP_001394621.1:p.Gln640Pro missense NM_001407694.1:c.1919A>C NP_001394623.1:p.Gln640Pro missense NM_001407695.1:c.1919A>C NP_001394624.1:p.Gln640Pro missense NM_001407696.1:c.1919A>C NP_001394625.1:p.Gln640Pro missense NM_001407697.1:c.1919A>C NP_001394626.1:p.Gln640Pro missense NM_001407698.1:c.1919A>C NP_001394627.1:p.Gln640Pro missense NM_001407724.1:c.1919A>C NP_001394653.1:p.Gln640Pro missense NM_001407725.1:c.1919A>C NP_001394654.1:p.Gln640Pro missense NM_001407726.1:c.1919A>C NP_001394655.1:p.Gln640Pro missense NM_001407727.1:c.1919A>C NP_001394656.1:p.Gln640Pro missense NM_001407728.1:c.1919A>C NP_001394657.1:p.Gln640Pro missense NM_001407729.1:c.1919A>C NP_001394658.1:p.Gln640Pro missense NM_001407730.1:c.1919A>C NP_001394659.1:p.Gln640Pro missense NM_001407731.1:c.1919A>C NP_001394660.1:p.Gln640Pro missense NM_001407732.1:c.1919A>C NP_001394661.1:p.Gln640Pro missense NM_001407733.1:c.1919A>C NP_001394662.1:p.Gln640Pro missense NM_001407734.1:c.1919A>C NP_001394663.1:p.Gln640Pro missense NM_001407735.1:c.1919A>C NP_001394664.1:p.Gln640Pro missense NM_001407736.1:c.1919A>C NP_001394665.1:p.Gln640Pro missense NM_001407737.1:c.1919A>C NP_001394666.1:p.Gln640Pro missense NM_001407738.1:c.1919A>C NP_001394667.1:p.Gln640Pro missense NM_001407739.1:c.1919A>C NP_001394668.1:p.Gln640Pro missense NM_001407740.1:c.1916A>C NP_001394669.1:p.Gln639Pro missense NM_001407741.1:c.1916A>C NP_001394670.1:p.Gln639Pro missense NM_001407742.1:c.1916A>C NP_001394671.1:p.Gln639Pro missense NM_001407743.1:c.1916A>C NP_001394672.1:p.Gln639Pro missense NM_001407744.1:c.1916A>C NP_001394673.1:p.Gln639Pro missense NM_001407745.1:c.1916A>C NP_001394674.1:p.Gln639Pro missense NM_001407746.1:c.1916A>C NP_001394675.1:p.Gln639Pro missense NM_001407747.1:c.1916A>C NP_001394676.1:p.Gln639Pro missense NM_001407748.1:c.1916A>C NP_001394677.1:p.Gln639Pro missense NM_001407749.1:c.1916A>C NP_001394678.1:p.Gln639Pro missense NM_001407750.1:c.1919A>C NP_001394679.1:p.Gln640Pro missense NM_001407751.1:c.1919A>C NP_001394680.1:p.Gln640Pro missense NM_001407752.1:c.1919A>C NP_001394681.1:p.Gln640Pro missense NM_001407838.1:c.1916A>C NP_001394767.1:p.Gln639Pro missense NM_001407839.1:c.1916A>C NP_001394768.1:p.Gln639Pro missense NM_001407841.1:c.1916A>C NP_001394770.1:p.Gln639Pro missense NM_001407842.1:c.1916A>C NP_001394771.1:p.Gln639Pro missense NM_001407843.1:c.1916A>C NP_001394772.1:p.Gln639Pro missense NM_001407844.1:c.1916A>C NP_001394773.1:p.Gln639Pro missense NM_001407845.1:c.1916A>C NP_001394774.1:p.Gln639Pro missense NM_001407846.1:c.1916A>C NP_001394775.1:p.Gln639Pro missense NM_001407847.1:c.1916A>C NP_001394776.1:p.Gln639Pro missense NM_001407848.1:c.1916A>C NP_001394777.1:p.Gln639Pro missense NM_001407849.1:c.1916A>C NP_001394778.1:p.Gln639Pro missense NM_001407850.1:c.1919A>C NP_001394779.1:p.Gln640Pro missense NM_001407851.1:c.1919A>C NP_001394780.1:p.Gln640Pro missense NM_001407852.1:c.1919A>C NP_001394781.1:p.Gln640Pro missense NM_001407853.1:c.1847A>C NP_001394782.1:p.Gln616Pro missense NM_001407854.1:c.2060A>C NP_001394783.1:p.Gln687Pro missense NM_001407858.1:c.2060A>C NP_001394787.1:p.Gln687Pro missense NM_001407859.1:c.2060A>C NP_001394788.1:p.Gln687Pro missense NM_001407860.1:c.2057A>C NP_001394789.1:p.Gln686Pro missense NM_001407861.1:c.2057A>C NP_001394790.1:p.Gln686Pro missense NM_001407862.1:c.1859A>C NP_001394791.1:p.Gln620Pro missense NM_001407863.1:c.1937A>C NP_001394792.1:p.Gln646Pro missense NM_001407874.1:c.1856A>C NP_001394803.1:p.Gln619Pro missense NM_001407875.1:c.1856A>C NP_001394804.1:p.Gln619Pro missense NM_001407879.1:c.1850A>C NP_001394808.1:p.Gln617Pro missense NM_001407881.1:c.1850A>C NP_001394810.1:p.Gln617Pro missense NM_001407882.1:c.1850A>C NP_001394811.1:p.Gln617Pro missense NM_001407884.1:c.1850A>C NP_001394813.1:p.Gln617Pro missense NM_001407885.1:c.1850A>C NP_001394814.1:p.Gln617Pro missense NM_001407886.1:c.1850A>C NP_001394815.1:p.Gln617Pro missense NM_001407887.1:c.1850A>C NP_001394816.1:p.Gln617Pro missense NM_001407889.1:c.1850A>C NP_001394818.1:p.Gln617Pro missense NM_001407894.1:c.1847A>C NP_001394823.1:p.Gln616Pro missense NM_001407895.1:c.1847A>C NP_001394824.1:p.Gln616Pro missense NM_001407896.1:c.1847A>C NP_001394825.1:p.Gln616Pro missense NM_001407897.1:c.1847A>C NP_001394826.1:p.Gln616Pro missense NM_001407898.1:c.1847A>C NP_001394827.1:p.Gln616Pro missense NM_001407899.1:c.1847A>C NP_001394828.1:p.Gln616Pro missense NM_001407900.1:c.1850A>C NP_001394829.1:p.Gln617Pro missense NM_001407902.1:c.1850A>C NP_001394831.1:p.Gln617Pro missense NM_001407904.1:c.1850A>C NP_001394833.1:p.Gln617Pro missense NM_001407906.1:c.1850A>C NP_001394835.1:p.Gln617Pro missense NM_001407907.1:c.1850A>C NP_001394836.1:p.Gln617Pro missense NM_001407908.1:c.1850A>C NP_001394837.1:p.Gln617Pro missense NM_001407909.1:c.1850A>C NP_001394838.1:p.Gln617Pro missense NM_001407910.1:c.1850A>C NP_001394839.1:p.Gln617Pro missense NM_001407915.1:c.1847A>C NP_001394844.1:p.Gln616Pro missense NM_001407916.1:c.1847A>C NP_001394845.1:p.Gln616Pro missense NM_001407917.1:c.1847A>C NP_001394846.1:p.Gln616Pro missense NM_001407918.1:c.1847A>C NP_001394847.1:p.Gln616Pro missense NM_001407919.1:c.1937A>C NP_001394848.1:p.Gln646Pro missense NM_001407920.1:c.1796A>C NP_001394849.1:p.Gln599Pro missense NM_001407921.1:c.1796A>C NP_001394850.1:p.Gln599Pro missense NM_001407922.1:c.1796A>C NP_001394851.1:p.Gln599Pro missense NM_001407923.1:c.1796A>C NP_001394852.1:p.Gln599Pro missense NM_001407924.1:c.1796A>C NP_001394853.1:p.Gln599Pro missense NM_001407925.1:c.1796A>C NP_001394854.1:p.Gln599Pro missense NM_001407926.1:c.1796A>C NP_001394855.1:p.Gln599Pro missense NM_001407927.1:c.1796A>C NP_001394856.1:p.Gln599Pro missense NM_001407928.1:c.1796A>C NP_001394857.1:p.Gln599Pro missense NM_001407929.1:c.1796A>C NP_001394858.1:p.Gln599Pro missense NM_001407930.1:c.1793A>C NP_001394859.1:p.Gln598Pro missense NM_001407931.1:c.1793A>C NP_001394860.1:p.Gln598Pro missense NM_001407932.1:c.1793A>C NP_001394861.1:p.Gln598Pro missense NM_001407933.1:c.1796A>C NP_001394862.1:p.Gln599Pro missense NM_001407934.1:c.1793A>C NP_001394863.1:p.Gln598Pro missense NM_001407935.1:c.1796A>C NP_001394864.1:p.Gln599Pro missense NM_001407936.1:c.1793A>C NP_001394865.1:p.Gln598Pro missense NM_001407937.1:c.1937A>C NP_001394866.1:p.Gln646Pro missense NM_001407938.1:c.1937A>C NP_001394867.1:p.Gln646Pro missense NM_001407939.1:c.1937A>C NP_001394868.1:p.Gln646Pro missense NM_001407940.1:c.1934A>C NP_001394869.1:p.Gln645Pro missense NM_001407941.1:c.1934A>C NP_001394870.1:p.Gln645Pro missense NM_001407942.1:c.1919A>C NP_001394871.1:p.Gln640Pro missense NM_001407943.1:c.1916A>C NP_001394872.1:p.Gln639Pro missense NM_001407944.1:c.1919A>C NP_001394873.1:p.Gln640Pro missense NM_001407945.1:c.1919A>C NP_001394874.1:p.Gln640Pro missense NM_001407946.1:c.1727A>C NP_001394875.1:p.Gln576Pro missense NM_001407947.1:c.1727A>C NP_001394876.1:p.Gln576Pro missense NM_001407948.1:c.1727A>C NP_001394877.1:p.Gln576Pro missense NM_001407949.1:c.1727A>C NP_001394878.1:p.Gln576Pro missense NM_001407950.1:c.1727A>C NP_001394879.1:p.Gln576Pro missense NM_001407951.1:c.1727A>C NP_001394880.1:p.Gln576Pro missense NM_001407952.1:c.1727A>C NP_001394881.1:p.Gln576Pro missense NM_001407953.1:c.1727A>C NP_001394882.1:p.Gln576Pro missense NM_001407954.1:c.1724A>C NP_001394883.1:p.Gln575Pro missense NM_001407955.1:c.1724A>C NP_001394884.1:p.Gln575Pro missense NM_001407956.1:c.1724A>C NP_001394885.1:p.Gln575Pro missense NM_001407957.1:c.1727A>C NP_001394886.1:p.Gln576Pro missense NM_001407958.1:c.1724A>C NP_001394887.1:p.Gln575Pro missense NM_001407959.1:c.1679A>C NP_001394888.1:p.Gln560Pro missense NM_001407960.1:c.1679A>C NP_001394889.1:p.Gln560Pro missense NM_001407962.1:c.1676A>C NP_001394891.1:p.Gln559Pro missense NM_001407963.1:c.1679A>C NP_001394892.1:p.Gln560Pro missense NM_001407964.1:c.1916A>C NP_001394893.1:p.Gln639Pro missense NM_001407965.1:c.1556A>C NP_001394894.1:p.Gln519Pro missense NM_001407966.1:c.1172A>C NP_001394895.1:p.Gln391Pro missense NM_001407967.1:c.1172A>C NP_001394896.1:p.Gln391Pro missense NM_001407968.1:c.787+1273A>C intron variant NM_001407969.1:c.787+1273A>C intron variant NM_001407970.1:c.787+1273A>C intron variant NM_001407971.1:c.787+1273A>C intron variant NM_001407972.1:c.784+1273A>C intron variant NM_001407973.1:c.787+1273A>C intron variant NM_001407974.1:c.787+1273A>C intron variant NM_001407975.1:c.787+1273A>C intron variant NM_001407976.1:c.787+1273A>C intron variant NM_001407977.1:c.787+1273A>C intron variant NM_001407978.1:c.787+1273A>C intron variant NM_001407979.1:c.787+1273A>C intron variant NM_001407980.1:c.787+1273A>C intron variant NM_001407981.1:c.787+1273A>C intron variant NM_001407982.1:c.787+1273A>C intron variant NM_001407983.1:c.787+1273A>C intron variant NM_001407984.1:c.784+1273A>C intron variant NM_001407985.1:c.784+1273A>C intron variant NM_001407986.1:c.784+1273A>C intron variant NM_001407990.1:c.787+1273A>C intron variant NM_001407991.1:c.784+1273A>C intron variant NM_001407992.1:c.784+1273A>C intron variant NM_001407993.1:c.787+1273A>C intron variant NM_001408392.1:c.784+1273A>C intron variant NM_001408396.1:c.784+1273A>C intron variant NM_001408397.1:c.784+1273A>C intron variant NM_001408398.1:c.784+1273A>C intron variant NM_001408399.1:c.784+1273A>C intron variant NM_001408400.1:c.784+1273A>C intron variant NM_001408401.1:c.784+1273A>C intron variant NM_001408402.1:c.784+1273A>C intron variant NM_001408403.1:c.787+1273A>C intron variant NM_001408404.1:c.787+1273A>C intron variant NM_001408406.1:c.790+1270A>C intron variant NM_001408407.1:c.784+1273A>C intron variant NM_001408408.1:c.778+1273A>C intron variant NM_001408409.1:c.709+1273A>C intron variant NM_001408410.1:c.646+1273A>C intron variant NM_001408411.1:c.709+1273A>C intron variant NM_001408412.1:c.709+1273A>C intron variant NM_001408413.1:c.706+1273A>C intron variant NM_001408414.1:c.709+1273A>C intron variant NM_001408415.1:c.709+1273A>C intron variant NM_001408416.1:c.706+1273A>C intron variant NM_001408418.1:c.670+2375A>C intron variant NM_001408419.1:c.670+2375A>C intron variant NM_001408420.1:c.670+2375A>C intron variant NM_001408421.1:c.667+2375A>C intron variant NM_001408422.1:c.670+2375A>C intron variant NM_001408423.1:c.670+2375A>C intron variant NM_001408424.1:c.667+2375A>C intron variant NM_001408425.1:c.664+1273A>C intron variant NM_001408426.1:c.664+1273A>C intron variant NM_001408427.1:c.664+1273A>C intron variant NM_001408428.1:c.664+1273A>C intron variant NM_001408429.1:c.664+1273A>C intron variant NM_001408430.1:c.664+1273A>C intron variant NM_001408431.1:c.667+2375A>C intron variant NM_001408432.1:c.661+1273A>C intron variant NM_001408433.1:c.661+1273A>C intron variant NM_001408434.1:c.661+1273A>C intron variant NM_001408435.1:c.661+1273A>C intron variant NM_001408436.1:c.664+1273A>C intron variant NM_001408437.1:c.664+1273A>C intron variant NM_001408438.1:c.664+1273A>C intron variant NM_001408439.1:c.664+1273A>C intron variant NM_001408440.1:c.664+1273A>C intron variant NM_001408441.1:c.664+1273A>C intron variant NM_001408442.1:c.664+1273A>C intron variant NM_001408443.1:c.664+1273A>C intron variant NM_001408444.1:c.664+1273A>C intron variant NM_001408445.1:c.661+1273A>C intron variant NM_001408446.1:c.661+1273A>C intron variant NM_001408447.1:c.661+1273A>C intron variant NM_001408448.1:c.661+1273A>C intron variant NM_001408450.1:c.661+1273A>C intron variant NM_001408451.1:c.652+1273A>C intron variant NM_001408452.1:c.646+1273A>C intron variant NM_001408453.1:c.646+1273A>C intron variant NM_001408454.1:c.646+1273A>C intron variant NM_001408455.1:c.646+1273A>C intron variant NM_001408456.1:c.646+1273A>C intron variant NM_001408457.1:c.646+1273A>C intron variant NM_001408458.1:c.646+1273A>C intron variant NM_001408459.1:c.646+1273A>C intron variant NM_001408460.1:c.646+1273A>C intron variant NM_001408461.1:c.646+1273A>C intron variant NM_001408462.1:c.643+1273A>C intron variant NM_001408463.1:c.643+1273A>C intron variant NM_001408464.1:c.643+1273A>C intron variant NM_001408465.1:c.643+1273A>C intron variant NM_001408466.1:c.646+1273A>C intron variant NM_001408467.1:c.646+1273A>C intron variant NM_001408468.1:c.643+1273A>C intron variant NM_001408469.1:c.646+1273A>C intron variant NM_001408470.1:c.643+1273A>C intron variant NM_001408472.1:c.787+1273A>C intron variant NM_001408473.1:c.784+1273A>C intron variant NM_001408474.1:c.586+1273A>C intron variant NM_001408475.1:c.583+1273A>C intron variant NM_001408476.1:c.586+1273A>C intron variant NM_001408478.1:c.577+1273A>C intron variant NM_001408479.1:c.577+1273A>C intron variant NM_001408480.1:c.577+1273A>C intron variant NM_001408481.1:c.577+1273A>C intron variant NM_001408482.1:c.577+1273A>C intron variant NM_001408483.1:c.577+1273A>C intron variant NM_001408484.1:c.577+1273A>C intron variant NM_001408485.1:c.577+1273A>C intron variant NM_001408489.1:c.577+1273A>C intron variant NM_001408490.1:c.574+1273A>C intron variant NM_001408491.1:c.574+1273A>C intron variant NM_001408492.1:c.577+1273A>C intron variant NM_001408493.1:c.574+1273A>C intron variant NM_001408494.1:c.548-2439A>C intron variant NM_001408495.1:c.545-2439A>C intron variant NM_001408496.1:c.523+1273A>C intron variant NM_001408497.1:c.523+1273A>C intron variant NM_001408498.1:c.523+1273A>C intron variant NM_001408499.1:c.523+1273A>C intron variant NM_001408500.1:c.523+1273A>C intron variant NM_001408501.1:c.523+1273A>C intron variant NM_001408502.1:c.454+1273A>C intron variant NM_001408503.1:c.520+1273A>C intron variant NM_001408504.1:c.520+1273A>C intron variant NM_001408505.1:c.520+1273A>C intron variant NM_001408506.1:c.460+2375A>C intron variant NM_001408507.1:c.460+2375A>C intron variant NM_001408508.1:c.451+1273A>C intron variant NM_001408509.1:c.451+1273A>C intron variant NM_001408510.1:c.406+1273A>C intron variant NM_001408511.1:c.404-2439A>C intron variant NM_001408512.1:c.283+1273A>C intron variant NM_001408513.1:c.577+1273A>C intron variant NM_001408514.1:c.577+1273A>C intron variant NM_007297.4:c.1919A>C NP_009228.2:p.Gln640Pro missense NM_007298.4:c.787+1273A>C intron variant NM_007299.4:c.787+1273A>C intron variant NM_007300.4:c.2060A>C NP_009231.2:p.Gln687Pro missense NR_027676.1:n.2196A>C NC_000017.11:g.43093471T>G NC_000017.10:g.41245488T>G NG_005905.2:g.124513A>C LRG_292:g.124513A>C LRG_292t1:c.2060A>C LRG_292p1:p.Gln687Pro U14680.1:n.2179A>C - Protein change
- Q687P, Q640P, Q560P, Q575P, Q599P, Q619P, Q639P, Q645P, Q646P, Q559P, Q686P, Q519P, Q598P, Q616P, Q617P, Q661P, Q391P, Q576P, Q620P, Q660P, Q684P
- Other names
-
p.Gln687Pro
2179A>C
- Canonical SPDI
- NC_000017.11:43093470:T:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (G)
-
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
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13044 | 14850 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, single submitter
|
Dec 18, 2023 | RCV000031024.18 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 3, 2024 | RCV000047696.22 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Apr 19, 2023 | RCV000129968.23 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 16, 2023 | RCV000587889.16 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 20, 2023 | RCV002281723.9 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Nov 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698913.3
First in ClinVar: Mar 17, 2018 Last updated: Jan 06, 2024 |
Comment:
Variant summary: BRCA1 c.2060A>C (p.Gln687Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: BRCA1 c.2060A>C (p.Gln687Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251304 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2060A>C has been reported in the literature as a VUS in a setting of BRCA1/2 gene panel testing at least one case of ovarian cancer, however whether the variant was germline or somatic was not determined (e.g. Ellison_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). A companion study, (Cline_2019) was also in agreement with this classification. However, to our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16518693, 31294896, 25859162, 20167696, 31112341, 15385441, 23704879). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=4; likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(Jun 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224364.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BP1, PM2
Number of individuals with the variant: 1
|
|
|
Likely benign
(Jan 03, 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: SCV000075709.13
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
|
|
|
Uncertain significance
(Dec 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184792.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.Q687P variant (also known as c.2060A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide … (more)
The p.Q687P variant (also known as c.2060A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 2060. The glutamine at codon 687 is replaced by proline, an amino acid with similar properties. This amino acid position is not 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)
|
|
|
Likely benign
(Mar 23, 2023)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV003849536.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Comment:
BRCA1 coldspot (exon 11 using historical exon numbering). Reclassification based on statistical prior probability
|
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
|
|
|
Uncertain significance
(Oct 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000565959.8
First in ClinVar: Apr 29, 2017 Last updated: Nov 25, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2179A>C; This variant is associated with the following publications: (PMID: 16518693, 17719744, 20668451, 20167696, 25859162, 35205643, 31294896, 15385441, 31112341, 31911673, 23704879, 15343273, 31131967) (less)
|
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Uncertain Significance
(Dec 18, 2023)
|
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: SCV004818229.1
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 glutamine with proline at codon 687 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces glutamine with proline at codon 687 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. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000181). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0673 and 0.311, respectively (PMID: 31131967). This variant has been identified in 3/282714 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)
Number of individuals with the variant: 7
|
|
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Uncertain significance
(Jun 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046409.2
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in an individual affected with breast cancer, as well as in an unaffected control individual, in … (more)
In the published literature, this variant has been reported in an individual affected with breast cancer, as well as in an unaffected control individual, in a large-scale association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)) and in an individual affected with pancreatic cancer (PMID: 35205643 (2022)). In addition, it was described as a likely benign variant in a multifactorial study (PMID: 31131967 (2019), see also LOVD (http://hci-exlovd.hci.utah.edu/)). The frequency of this variant in the general population, 0.000023 (3/129072 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
(Apr 19, 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: SCV000683009.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamine with proline at codon 687 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces glutamine with proline at codon 687 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. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000181). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0673 and 0.311, respectively (PMID: 31131967). This variant has been identified in 3/282714 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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Likely benign
(Mar 15, 2010)
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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: SCV000053617.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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Uncertain significance
(May 29, 2002)
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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: SCV000144283.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
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Comment:
Comment:
BP1, PM2
Comment:
The p.Q687P variant (also known as c.2060A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 2060. The glutamine at codon 687 is replaced by proline, an amino acid with similar properties. This amino acid position is not 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.
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2179A>C; This variant is associated with the following publications: (PMID: 16518693, 17719744, 20668451, 20167696, 25859162, 35205643, 31294896, 15385441, 31112341, 31911673, 23704879, 15343273, 31131967)
Comment:
This missense variant replaces glutamine with proline at codon 687 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. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000181). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0673 and 0.311, respectively (PMID: 31131967). This variant has been identified in 3/282714 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:
In the published literature, this variant has been reported in an individual affected with breast cancer, as well as in an unaffected control individual, in a large-scale association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)) and in an individual affected with pancreatic cancer (PMID: 35205643 (2022)). In addition, it was described as a likely benign variant in a multifactorial study (PMID: 31131967 (2019), see also LOVD (http://hci-exlovd.hci.utah.edu/)). The frequency of this variant in the general population, 0.000023 (3/129072 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 glutamine with proline at codon 687 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. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000181). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0673 and 0.311, respectively (PMID: 31131967). This variant has been identified in 3/282714 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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: BRCA1 c.2060A>C (p.Gln687Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251304 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2060A>C has been reported in the literature as a VUS in a setting of BRCA1/2 gene panel testing at least one case of ovarian cancer, however whether the variant was germline or somatic was not determined (e.g. Ellison_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). A companion study, (Cline_2019) was also in agreement with this classification. However, to our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16518693, 31294896, 25859162, 20167696, 31112341, 15385441, 23704879). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=4; likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
BP1, PM2
Comment:
The p.Q687P variant (also known as c.2060A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 2060. The glutamine at codon 687 is replaced by proline, an amino acid with similar properties. This amino acid position is not 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.
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2179A>C; This variant is associated with the following publications: (PMID: 16518693, 17719744, 20668451, 20167696, 25859162, 35205643, 31294896, 15385441, 31112341, 31911673, 23704879, 15343273, 31131967)
Comment:
This missense variant replaces glutamine with proline at codon 687 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. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000181). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0673 and 0.311, respectively (PMID: 31131967). This variant has been identified in 3/282714 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:
In the published literature, this variant has been reported in an individual affected with breast cancer, as well as in an unaffected control individual, in a large-scale association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)) and in an individual affected with pancreatic cancer (PMID: 35205643 (2022)). In addition, it was described as a likely benign variant in a multifactorial study (PMID: 31131967 (2019), see also LOVD (http://hci-exlovd.hci.utah.edu/)). The frequency of this variant in the general population, 0.000023 (3/129072 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 glutamine with proline at codon 687 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. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000181). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0673 and 0.311, respectively (PMID: 31131967). This variant has been identified in 3/282714 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Precision Medicine for BRCA/PALB2-Mutated Pancreatic Cancer and Emerging Strategies to Improve Therapeutic Responses to PARP Inhibition. | Principe DR | Cancers | 2022 | PMID: 35205643 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance. | Lyra PCM Jr | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33087888 |
| Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". | Dines JN | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31911673 |
| Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort. | Li H | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31853058 |
| Assessment of blind predictions of the clinical significance of BRCA1 and BRCA2 variants. | Cline MS | Human mutation | 2019 | PMID: 31294896 |
| 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 |
| BRCA1- and BRCA2-specific in silico tools for variant interpretation in the CAGI 5 ENIGMA challenge. | Padilla N | Human mutation | 2019 | PMID: 31112341 |
| A reliable method for the detection of BRCA1 and BRCA2 mutations in fixed tumour tissue utilising multiplex PCR-based targeted next generation sequencing. | Ellison G | BMC clinical pathology | 2015 | PMID: 25859162 |
| Missense variants of uncertain significance (VUS) altering the phosphorylation patterns of BRCA1 and BRCA2. | Tram E | PloS one | 2013 | PMID: 23704879 |
| Interlaboratory diagnostic validation of conformation-sensitive capillary electrophoresis for mutation scanning. | Mattocks CJ | Clinical chemistry | 2010 | PMID: 20167696 |
| Identification and in silico analysis of functional SNPs of the BRCA1 gene. | Rajasekaran R | Genomics | 2007 | PMID: 17719744 |
| Natural selection and mammalian BRCA1 sequences: elucidating functionally important sites relevant to breast cancer susceptibility in humans. | Burk-Herrick A | Mammalian genome : official journal of the International Mammalian Genome Society | 2006 | PMID: 16518693 |
| Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition. | Pavlicek A | Human molecular genetics | 2004 | PMID: 15385441 |
| The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
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Text-mined citations for rs28897680 ...
HelpThese citations are identified by LitVar using
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variant of interest.
Record last updated Nov 10, 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.