VCV000037449.39 - ClinVar

NM_007294.4(BRCA1):c.213-11T>G

Germline

Classification

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.

(20)

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

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.213-11T>G

Variation ID: 37449 Accession: VCV000037449.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.31 17: 43104967 (GRCh38) [ NCBI UCSC ] 17: 41256984 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 1, 2014	Oct 8, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007294.4:c.213-11T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001407571.1:c.3-11T>G		intron variant
NM_001407581.1:c.213-11T>G		intron variant
NM_001407582.1:c.213-11T>G		intron variant
NM_001407583.1:c.213-11T>G		intron variant
NM_001407585.1:c.213-11T>G		intron variant
NM_001407587.1:c.213-11T>G		intron variant
NM_001407590.1:c.213-11T>G		intron variant
NM_001407591.1:c.213-11T>G		intron variant
NM_001407593.1:c.213-11T>G		intron variant
NM_001407594.1:c.213-11T>G		intron variant
NM_001407596.1:c.213-11T>G		intron variant
NM_001407597.1:c.213-11T>G		intron variant
NM_001407598.1:c.213-11T>G		intron variant
NM_001407602.1:c.213-11T>G		intron variant
NM_001407603.1:c.213-11T>G		intron variant
NM_001407605.1:c.213-11T>G		intron variant
NM_001407610.1:c.213-11T>G		intron variant
NM_001407611.1:c.213-11T>G		intron variant
NM_001407612.1:c.213-11T>G		intron variant
NM_001407613.1:c.213-11T>G		intron variant
NM_001407614.1:c.213-11T>G		intron variant
NM_001407615.1:c.213-11T>G		intron variant
NM_001407616.1:c.213-11T>G		intron variant
NM_001407617.1:c.213-11T>G		intron variant
NM_001407618.1:c.213-11T>G		intron variant
NM_001407619.1:c.213-11T>G		intron variant
NM_001407620.1:c.213-11T>G		intron variant
NM_001407621.1:c.213-11T>G		intron variant
NM_001407622.1:c.213-11T>G		intron variant
NM_001407623.1:c.213-11T>G		intron variant
NM_001407624.1:c.213-11T>G		intron variant
NM_001407625.1:c.213-11T>G		intron variant
NM_001407626.1:c.213-11T>G		intron variant
NM_001407627.1:c.213-11T>G		intron variant
NM_001407628.1:c.213-11T>G		intron variant
NM_001407629.1:c.213-11T>G		intron variant
NM_001407630.1:c.213-11T>G		intron variant
NM_001407631.1:c.213-11T>G		intron variant
NM_001407632.1:c.213-11T>G		intron variant
NM_001407633.1:c.213-11T>G		intron variant
NM_001407634.1:c.213-11T>G		intron variant
NM_001407635.1:c.213-11T>G		intron variant
NM_001407636.1:c.213-11T>G		intron variant
NM_001407637.1:c.213-11T>G		intron variant
NM_001407638.1:c.213-11T>G		intron variant
NM_001407639.1:c.213-11T>G		intron variant
NM_001407640.1:c.213-11T>G		intron variant
NM_001407641.1:c.213-11T>G		intron variant
NM_001407642.1:c.213-11T>G		intron variant
NM_001407644.1:c.213-11T>G		intron variant
NM_001407645.1:c.213-11T>G		intron variant
NM_001407646.1:c.213-11T>G		intron variant
NM_001407647.1:c.213-11T>G		intron variant
NM_001407648.1:c.213-11T>G		intron variant
NM_001407649.1:c.213-11T>G		intron variant
NM_001407652.1:c.213-11T>G		intron variant
NM_001407653.1:c.135-11T>G		intron variant
NM_001407654.1:c.135-11T>G		intron variant
NM_001407655.1:c.135-11T>G		intron variant
NM_001407656.1:c.135-11T>G		intron variant
NM_001407657.1:c.135-11T>G		intron variant
NM_001407658.1:c.135-11T>G		intron variant
NM_001407659.1:c.135-11T>G		intron variant
NM_001407660.1:c.135-11T>G		intron variant
NM_001407661.1:c.135-11T>G		intron variant
NM_001407662.1:c.135-11T>G		intron variant
NM_001407663.1:c.135-11T>G		intron variant
NM_001407664.1:c.213-11T>G		intron variant
NM_001407665.1:c.213-11T>G		intron variant
NM_001407666.1:c.213-11T>G		intron variant
NM_001407667.1:c.213-11T>G		intron variant
NM_001407668.1:c.213-11T>G		intron variant
NM_001407669.1:c.213-11T>G		intron variant
NM_001407670.1:c.213-11T>G		intron variant
NM_001407671.1:c.213-11T>G		intron variant
NM_001407672.1:c.213-11T>G		intron variant
NM_001407673.1:c.213-11T>G		intron variant
NM_001407674.1:c.213-11T>G		intron variant
NM_001407675.1:c.213-11T>G		intron variant
NM_001407676.1:c.213-11T>G		intron variant
NM_001407677.1:c.213-11T>G		intron variant
NM_001407678.1:c.213-11T>G		intron variant
NM_001407679.1:c.213-11T>G		intron variant
NM_001407680.1:c.213-11T>G		intron variant
NM_001407681.1:c.213-11T>G		intron variant
NM_001407682.1:c.213-11T>G		intron variant
NM_001407683.1:c.213-11T>G		intron variant
NM_001407684.1:c.213-11T>G		intron variant
NM_001407685.1:c.213-11T>G		intron variant
NM_001407686.1:c.213-11T>G		intron variant
NM_001407687.1:c.213-11T>G		intron variant
NM_001407688.1:c.213-11T>G		intron variant
NM_001407689.1:c.213-11T>G		intron variant
NM_001407690.1:c.213-11T>G		intron variant
NM_001407691.1:c.213-11T>G		intron variant
NM_001407692.1:c.72-11T>G		intron variant
NM_001407694.1:c.72-11T>G		intron variant
NM_001407695.1:c.72-11T>G		intron variant
NM_001407696.1:c.72-11T>G		intron variant
NM_001407697.1:c.72-11T>G		intron variant
NM_001407698.1:c.72-11T>G		intron variant
NM_001407724.1:c.72-11T>G		intron variant
NM_001407725.1:c.72-11T>G		intron variant
NM_001407726.1:c.72-11T>G		intron variant
NM_001407727.1:c.72-11T>G		intron variant
NM_001407728.1:c.72-11T>G		intron variant
NM_001407729.1:c.72-11T>G		intron variant
NM_001407730.1:c.72-11T>G		intron variant
NM_001407731.1:c.72-11T>G		intron variant
NM_001407732.1:c.72-11T>G		intron variant
NM_001407733.1:c.72-11T>G		intron variant
NM_001407734.1:c.72-11T>G		intron variant
NM_001407735.1:c.72-11T>G		intron variant
NM_001407736.1:c.72-11T>G		intron variant
NM_001407737.1:c.72-11T>G		intron variant
NM_001407738.1:c.72-11T>G		intron variant
NM_001407739.1:c.72-11T>G		intron variant
NM_001407740.1:c.72-11T>G		intron variant
NM_001407741.1:c.72-11T>G		intron variant
NM_001407742.1:c.72-11T>G		intron variant
NM_001407743.1:c.72-11T>G		intron variant
NM_001407744.1:c.72-11T>G		intron variant
NM_001407745.1:c.72-11T>G		intron variant
NM_001407746.1:c.72-11T>G		intron variant
NM_001407747.1:c.72-11T>G		intron variant
NM_001407748.1:c.72-11T>G		intron variant
NM_001407749.1:c.72-11T>G		intron variant
NM_001407750.1:c.72-11T>G		intron variant
NM_001407751.1:c.72-11T>G		intron variant
NM_001407752.1:c.72-11T>G		intron variant
NM_001407838.1:c.72-11T>G		intron variant
NM_001407839.1:c.72-11T>G		intron variant
NM_001407841.1:c.72-11T>G		intron variant
NM_001407842.1:c.72-11T>G		intron variant
NM_001407843.1:c.72-11T>G		intron variant
NM_001407844.1:c.72-11T>G		intron variant
NM_001407845.1:c.72-11T>G		intron variant
NM_001407846.1:c.72-11T>G		intron variant
NM_001407847.1:c.72-11T>G		intron variant
NM_001407848.1:c.72-11T>G		intron variant
NM_001407849.1:c.72-11T>G		intron variant
NM_001407850.1:c.72-11T>G		intron variant
NM_001407851.1:c.72-11T>G		intron variant
NM_001407852.1:c.72-11T>G		intron variant
NM_001407853.1:c.3-11T>G		intron variant
NM_001407854.1:c.213-11T>G		intron variant
NM_001407858.1:c.213-11T>G		intron variant
NM_001407859.1:c.213-11T>G		intron variant
NM_001407860.1:c.213-11T>G		intron variant
NM_001407861.1:c.213-11T>G		intron variant
NM_001407862.1:c.135-11T>G		intron variant
NM_001407863.1:c.213-11T>G		intron variant
NM_001407874.1:c.135-11T>G		intron variant
NM_001407875.1:c.135-11T>G		intron variant
NM_001407879.1:c.3-11T>G		intron variant
NM_001407881.1:c.3-11T>G		intron variant
NM_001407882.1:c.3-11T>G		intron variant
NM_001407884.1:c.3-11T>G		intron variant
NM_001407885.1:c.3-11T>G		intron variant
NM_001407886.1:c.3-11T>G		intron variant
NM_001407887.1:c.3-11T>G		intron variant
NM_001407889.1:c.3-11T>G		intron variant
NM_001407894.1:c.3-11T>G		intron variant
NM_001407895.1:c.3-11T>G		intron variant
NM_001407896.1:c.3-11T>G		intron variant
NM_001407897.1:c.3-11T>G		intron variant
NM_001407898.1:c.3-11T>G		intron variant
NM_001407899.1:c.3-11T>G		intron variant
NM_001407900.1:c.3-11T>G		intron variant
NM_001407902.1:c.3-11T>G		intron variant
NM_001407904.1:c.3-11T>G		intron variant
NM_001407906.1:c.3-11T>G		intron variant
NM_001407907.1:c.3-11T>G		intron variant
NM_001407908.1:c.3-11T>G		intron variant
NM_001407909.1:c.3-11T>G		intron variant
NM_001407910.1:c.3-11T>G		intron variant
NM_001407915.1:c.3-11T>G		intron variant
NM_001407916.1:c.3-11T>G		intron variant
NM_001407917.1:c.3-11T>G		intron variant
NM_001407918.1:c.3-11T>G		intron variant
NM_001407919.1:c.213-11T>G		intron variant
NM_001407920.1:c.72-11T>G		intron variant
NM_001407921.1:c.72-11T>G		intron variant
NM_001407922.1:c.72-11T>G		intron variant
NM_001407923.1:c.72-11T>G		intron variant
NM_001407924.1:c.72-11T>G		intron variant
NM_001407925.1:c.72-11T>G		intron variant
NM_001407926.1:c.72-11T>G		intron variant
NM_001407927.1:c.72-11T>G		intron variant
NM_001407928.1:c.72-11T>G		intron variant
NM_001407929.1:c.72-11T>G		intron variant
NM_001407930.1:c.72-11T>G		intron variant
NM_001407931.1:c.72-11T>G		intron variant
NM_001407932.1:c.72-11T>G		intron variant
NM_001407933.1:c.72-11T>G		intron variant
NM_001407934.1:c.72-11T>G		intron variant
NM_001407935.1:c.72-11T>G		intron variant
NM_001407936.1:c.72-11T>G		intron variant
NM_001407937.1:c.213-11T>G		intron variant
NM_001407938.1:c.213-11T>G		intron variant
NM_001407939.1:c.213-11T>G		intron variant
NM_001407940.1:c.213-11T>G		intron variant
NM_001407941.1:c.213-11T>G		intron variant
NM_001407942.1:c.72-11T>G		intron variant
NM_001407943.1:c.72-11T>G		intron variant
NM_001407944.1:c.72-11T>G		intron variant
NM_001407945.1:c.72-11T>G		intron variant
NM_001407946.1:c.3-11T>G		intron variant
NM_001407947.1:c.3-11T>G		intron variant
NM_001407948.1:c.3-11T>G		intron variant
NM_001407949.1:c.3-11T>G		intron variant
NM_001407950.1:c.3-11T>G		intron variant
NM_001407951.1:c.3-11T>G		intron variant
NM_001407952.1:c.3-11T>G		intron variant
NM_001407953.1:c.3-11T>G		intron variant
NM_001407954.1:c.3-11T>G		intron variant
NM_001407955.1:c.3-11T>G		intron variant
NM_001407956.1:c.3-11T>G		intron variant
NM_001407957.1:c.3-11T>G		intron variant
NM_001407958.1:c.3-11T>G		intron variant
NM_001407959.1:c.-169-11T>G		intron variant
NM_001407960.1:c.-169-11T>G		intron variant
NM_001407962.1:c.-169-11T>G		intron variant
NM_001407963.1:c.-169-11T>G		intron variant
NM_001407964.1:c.72-11T>G		intron variant
NM_001407965.1:c.-169-11T>G		intron variant
NM_001407966.1:c.-218-10107T>G		intron variant
NM_001407967.1:c.-218-10107T>G		intron variant
NM_001407968.1:c.213-11T>G		intron variant
NM_001407969.1:c.213-11T>G		intron variant
NM_001407970.1:c.213-11T>G		intron variant
NM_001407971.1:c.213-11T>G		intron variant
NM_001407972.1:c.213-11T>G		intron variant
NM_001407973.1:c.213-11T>G		intron variant
NM_001407974.1:c.213-11T>G		intron variant
NM_001407975.1:c.213-11T>G		intron variant
NM_001407976.1:c.213-11T>G		intron variant
NM_001407977.1:c.213-11T>G		intron variant
NM_001407978.1:c.213-11T>G		intron variant
NM_001407979.1:c.213-11T>G		intron variant
NM_001407980.1:c.213-11T>G		intron variant
NM_001407981.1:c.213-11T>G		intron variant
NM_001407982.1:c.213-11T>G		intron variant
NM_001407983.1:c.213-11T>G		intron variant
NM_001407984.1:c.213-11T>G		intron variant
NM_001407985.1:c.213-11T>G		intron variant
NM_001407986.1:c.213-11T>G		intron variant
NM_001407990.1:c.213-11T>G		intron variant
NM_001407991.1:c.213-11T>G		intron variant
NM_001407992.1:c.213-11T>G		intron variant
NM_001407993.1:c.213-11T>G		intron variant
NM_001408392.1:c.213-11T>G		intron variant
NM_001408396.1:c.213-11T>G		intron variant
NM_001408397.1:c.213-11T>G		intron variant
NM_001408398.1:c.213-11T>G		intron variant
NM_001408399.1:c.213-11T>G		intron variant
NM_001408400.1:c.213-11T>G		intron variant
NM_001408401.1:c.213-11T>G		intron variant
NM_001408402.1:c.213-11T>G		intron variant
NM_001408403.1:c.213-11T>G		intron variant
NM_001408404.1:c.213-11T>G		intron variant
NM_001408406.1:c.213-11T>G		intron variant
NM_001408407.1:c.213-11T>G		intron variant
NM_001408408.1:c.213-11T>G		intron variant
NM_001408409.1:c.135-11T>G		intron variant
NM_001408410.1:c.72-11T>G		intron variant
NM_001408411.1:c.135-11T>G		intron variant
NM_001408412.1:c.135-11T>G		intron variant
NM_001408413.1:c.135-11T>G		intron variant
NM_001408414.1:c.135-11T>G		intron variant
NM_001408415.1:c.135-11T>G		intron variant
NM_001408416.1:c.135-11T>G		intron variant
NM_001408418.1:c.213-11T>G		intron variant
NM_001408419.1:c.213-11T>G		intron variant
NM_001408420.1:c.213-11T>G		intron variant
NM_001408421.1:c.213-11T>G		intron variant
NM_001408422.1:c.213-11T>G		intron variant
NM_001408423.1:c.213-11T>G		intron variant
NM_001408424.1:c.213-11T>G		intron variant
NM_001408425.1:c.213-11T>G		intron variant
NM_001408426.1:c.213-11T>G		intron variant
NM_001408427.1:c.213-11T>G		intron variant
NM_001408428.1:c.213-11T>G		intron variant
NM_001408429.1:c.213-11T>G		intron variant
NM_001408430.1:c.213-11T>G		intron variant
NM_001408431.1:c.213-11T>G		intron variant
NM_001408432.1:c.213-11T>G		intron variant
NM_001408433.1:c.213-11T>G		intron variant
NM_001408434.1:c.213-11T>G		intron variant
NM_001408435.1:c.213-11T>G		intron variant
NM_001408436.1:c.213-11T>G		intron variant
NM_001408437.1:c.213-11T>G		intron variant
NM_001408438.1:c.213-11T>G		intron variant
NM_001408439.1:c.213-11T>G		intron variant
NM_001408440.1:c.213-11T>G		intron variant
NM_001408441.1:c.213-11T>G		intron variant
NM_001408442.1:c.213-11T>G		intron variant
NM_001408443.1:c.213-11T>G		intron variant
NM_001408444.1:c.213-11T>G		intron variant
NM_001408445.1:c.213-11T>G		intron variant
NM_001408446.1:c.213-11T>G		intron variant
NM_001408447.1:c.213-11T>G		intron variant
NM_001408448.1:c.213-11T>G		intron variant
NM_001408450.1:c.213-11T>G		intron variant
NM_001408451.1:c.81-11T>G		intron variant
NM_001408452.1:c.72-11T>G		intron variant
NM_001408453.1:c.72-11T>G		intron variant
NM_001408454.1:c.72-11T>G		intron variant
NM_001408455.1:c.72-11T>G		intron variant
NM_001408456.1:c.72-11T>G		intron variant
NM_001408457.1:c.72-11T>G		intron variant
NM_001408458.1:c.72-11T>G		intron variant
NM_001408459.1:c.72-11T>G		intron variant
NM_001408460.1:c.72-11T>G		intron variant
NM_001408461.1:c.72-11T>G		intron variant
NM_001408462.1:c.72-11T>G		intron variant
NM_001408463.1:c.72-11T>G		intron variant
NM_001408464.1:c.72-11T>G		intron variant
NM_001408465.1:c.72-11T>G		intron variant
NM_001408466.1:c.72-11T>G		intron variant
NM_001408467.1:c.72-11T>G		intron variant
NM_001408468.1:c.72-11T>G		intron variant
NM_001408469.1:c.72-11T>G		intron variant
NM_001408470.1:c.72-11T>G		intron variant
NM_001408472.1:c.213-11T>G		intron variant
NM_001408473.1:c.213-11T>G		intron variant
NM_001408474.1:c.135-11T>G		intron variant
NM_001408475.1:c.135-11T>G		intron variant
NM_001408476.1:c.135-11T>G		intron variant
NM_001408478.1:c.3-11T>G		intron variant
NM_001408479.1:c.3-11T>G		intron variant
NM_001408480.1:c.3-11T>G		intron variant
NM_001408481.1:c.3-11T>G		intron variant
NM_001408482.1:c.3-11T>G		intron variant
NM_001408483.1:c.3-11T>G		intron variant
NM_001408484.1:c.3-11T>G		intron variant
NM_001408485.1:c.3-11T>G		intron variant
NM_001408489.1:c.3-11T>G		intron variant
NM_001408490.1:c.3-11T>G		intron variant
NM_001408491.1:c.3-11T>G		intron variant
NM_001408492.1:c.3-11T>G		intron variant
NM_001408493.1:c.3-11T>G		intron variant
NM_001408494.1:c.213-11T>G		intron variant
NM_001408495.1:c.213-11T>G		intron variant
NM_001408496.1:c.72-11T>G		intron variant
NM_001408497.1:c.72-11T>G		intron variant
NM_001408498.1:c.72-11T>G		intron variant
NM_001408499.1:c.72-11T>G		intron variant
NM_001408500.1:c.72-11T>G		intron variant
NM_001408501.1:c.72-11T>G		intron variant
NM_001408502.1:c.3-11T>G		intron variant
NM_001408503.1:c.72-11T>G		intron variant
NM_001408504.1:c.72-11T>G		intron variant
NM_001408505.1:c.72-11T>G		intron variant
NM_001408506.1:c.3-11T>G		intron variant
NM_001408507.1:c.3-11T>G		intron variant
NM_001408508.1:c.3-11T>G		intron variant
NM_001408509.1:c.3-11T>G		intron variant
NM_001408510.1:c.-169-11T>G		intron variant
NM_001408511.1:c.72-11T>G		intron variant
NM_001408512.1:c.-169-11T>G		intron variant
NM_001408513.1:c.3-11T>G		intron variant
NM_001408514.1:c.3-11T>G		intron variant
NM_007297.4:c.72-11T>G		intron variant
NM_007298.4:c.213-11T>G		intron variant
NM_007299.4:c.213-11T>G		intron variant
NM_007300.4:c.213-11T>G		intron variant
NC_000017.11:g.43104967A>C
NC_000017.10:g.41256984A>C
NG_005905.2:g.113017T>G
LRG_292:g.113017T>G
LRG_292t1:c.213-11T>G
U14680.1:n.332-11T>G

... more HGVS ... less HGVS

Protein change

Other names

IVS4-11 T>G
IVS5-11T>G

Canonical SPDI

NC_000017.11:43104966:A:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

Breast Cancer Information Core (BIC) (BRCA1): 332-11&base_change=T to G ClinGen: CA001424 OMIM: 113705.0004 dbSNP: rs80358061 VarSome

Comment on variant

NCBI staff could not confirm the published nucleotide change on current reference sequence after review of PubMed 7894493.

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
Gene	OMIM	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.
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Dec 14, 2023	RCV000031030.22
Hereditary breast ovarian cancer syndrome	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 30, 2024	RCV000047725.32
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 10, 2023	RCV000074570.27
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 10, 2023	RCV000131898.17
Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	Feb 23, 2017	RCV000469831.9
Breast and/or ovarian cancer	Pathogenic (1)	no assertion criteria provided	Jan 26, 2007	RCV000735531.9
BRCA1-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 23, 2024	RCV004758603.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 15, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) 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: SCV000698919.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (9) PubMed: 21993507‚ 22505045‚ 7894493‚ 22430266‚ 21702907‚ 24667779‚ 16528604‚ 23451180‚ 18424508 Comment: Variant summary: The BRCA1 c.213-11T>G variant affects a conserved intronic nucleotide. 3/5 splice-site tools predict the variant to create a new cryptic splice site and/or … (more) Variant summary: The BRCA1 c.213-11T>G variant affects a conserved intronic nucleotide. 3/5 splice-site tools predict the variant to create a new cryptic splice site and/or weaken the cononical splice site. This in silico predicted result is proven by multiple functional studies showing that this variant leads to a splicing defect, resulting in an extra 59 base pairs at the end of intron 4 and introducing a premature stop codon. This variant was found in 1/121156 control chromosomes at a frequency of 0.0000083, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). However, the variant has been found in multiple HBOC patients or individuals undergoing BRCA1/2 testing as reported in literature and clinical databases. Additionally, several clinical labs and clinical databases have classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic. (less)
Pathogenic (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000075738.17 First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 28492532‚ 7894493‚ 10923033‚ 18284688‚ 21993507‚ 22144684‚ 25452441‚ 18424508‚ 23451180 Comment: This sequence change falls in intron 4 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. … (more) This sequence change falls in intron 4 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80358061, gnomAD 0.003%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7894493, 10923033, 18284688, 21993507, 22144684, 25452441). It has also been observed to segregate with disease in related individuals. This variant is also known as c.332-11T>G and IVS5-11T>G. ClinVar contains an entry for this variant (Variation ID: 37449). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 18424508, 23451180; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 10, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602679.4 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: The BRCA1 c.213-11T>G variant, also known as 332-11T>G or IVS5-11T>G, is reported in the medical literature in multiple individuals and families with breast and/or ovarian … (more) The BRCA1 c.213-11T>G variant, also known as 332-11T>G or IVS5-11T>G, is reported in the medical literature in multiple individuals and families with breast and/or ovarian cancer (Carter 2018, Friedman 1994, Yost 2019). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37449). This variant is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, in silico analyses and experimental evidence demonstrate this variant causes aberrant intronic splicing (Bonnet 2008, Colombo 2013). Based on available information, this variant is classified as pathogenic. References: Bonnet C et al. Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene. J Med Genet. 2008 Jul;45(7):438-46. PMID: 18424508. Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Colombo M et al. Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. PLoS One. 2013;8(2):e57173. PMID: 23451180. Friedman LS et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet. 1994 Dec;8(4):399-404. PMID: 7894493. Yost S et al. Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers. JNCI Cancer Spectr. 2019 Apr 19;3(2):pkz028. PMID: 31360904. (less)
Pathogenic (Nov 30, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000186953.6 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 25682074‚ 26296701‚ 27062684 Comment: The c.213-11T>G intronic pathogenic mutation results from a T to G substitution eleven nucleotides before coding exon 4 of the BRCA1 gene. In three in … (more) The c.213-11T>G intronic pathogenic mutation results from a T to G substitution eleven nucleotides before coding exon 4 of the BRCA1 gene. In three in vitro studies, this mutation was found to activate a cryptic splice site that leads to the retention of 59 base pairs at the 5' end of coding exon 4, leading to a premature stop codon and a truncated protein product (Colombo M et al. PLoS One. 2013 Mar;8:e57173; Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). In addition, this mutation has been observed in multiple breast and ovarian cancer families to date (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Ellingson MS et al. Breast Cancer Res. Treat. 2015 Sep;153:435-43; Hall MJ et al. Cancer. 2009 May;115:2222-33; John EM et al. JAMA. 2007 Dec;298:2869-76; Musolino A et al. Tumori. 2005 Nov-Dec;91:505-12), including one in which this mutation was reported to segregate with disease through three generations (Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404). Of note, this mutation is also designated as IVS5-11T>G and 75Stop in published literature. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Feb 23, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Baylor Genetics Accession: SCV000540930.1 First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017	Number of individuals with the variant: 1
Pathogenic (Sep 12, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000108655.12 First in ClinVar: Dec 10, 2013 Last updated: Dec 19, 2017	Comment: This pathogenic variant is denoted BRCA1 c.213-11T>G or IVS4-11T>G and consists of a T>G nucleotide substitution at the -11 position of intron 4 of the … (more) This pathogenic variant is denoted BRCA1 c.213-11T>G or IVS4-11T>G and consists of a T>G nucleotide substitution at the -11 position of intron 4 of the BRCA1 gene. This variant is also known as BRCA1 332-11T>G or BRCA1 IVS5-11T>G using alternate nomenclature. RNA and minigene assays have demonstrated that BRCA1 c.213-11T>G causes aberrant splicing through activation of a cryptic splice acceptor site, introducing a premature stop codon and leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Bonnet 2008, Colombo 2013). This variant has been observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer, and has been shown to segregate with disease (Friedman 1994, Musolino 2005, John 2007, Colombo 2013, Song 2014, Wong-Brown 2015). We consider this variant to be pathogenic. (less)
Pathogenic (Jul 20, 2017)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hereditary breast ovarian cancer syndrome (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000966958.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (5) PubMed: 23451180‚ 18159056‚ 25682074‚ 7894493‚ 21993507 Comment: The c.213-11T>G variant in BRCA1 has been reported in >100 individuals with BRCA 1-associated cancers and has segregated with disease in multiple affected relati ves … (more) The c.213-11T>G variant in BRCA1 has been reported in >100 individuals with BRCA 1-associated cancers and has segregated with disease in multiple affected relati ves (Friedman 1994, John 2007, Smith 2012, Wong-Brown 2015, BIC database). This variant has also been reported by multiple clinical laboratories in ClinVar (Var iation ID# 37449). Additionally, this variant has been identified in 3/111540 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org). Sequencing of patient RNA has shown that this variant leads to a retention of 59 base pairs at the 3' end of intron 5, which is predicted to r esult in a premature stop codon (Friedman 1994, Colombo 2013). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individual s with hereditary breast and/or ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the frequency in patients and segregation studies. ACMG/AMP cr iteria applied: PS4, PP1_Strong. (less) Number of individuals with the variant: 2
Pathogenic (Oct 24, 2014)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: literature only	Breast-ovarian cancer, familial 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220836.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (8) PubMed: 23451180‚ 22505045‚ 7894493‚ 19241424‚ 18284688‚ 16267036‚ 18424508‚ 18159056
Pathogenic (May 10, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000296273.7 First in ClinVar: Mar 29, 2015 Last updated: Jan 06, 2024	Publications: PubMed (26) PubMed: 26295337‚ 25452441‚ 27062684‚ 25682074‚ 16457150‚ 18159056‚ 24728189‚ 22505045‚ 18424508‚ 21993507‚ 21702907‚ 18824701‚ 21170264‚ 16544996‚ 12112659‚ 7894493‚ 23451180‚ 22711857‚ 25525159‚ 30322717‚ 30720243‚ 31360904‚ 31447099‚ 31850619‚ 32719484‚ 33484353 Comment: This variant has been reported in hereditary breast/ovarian cancer families in the published literature (PMIDs: 7894493 (1994), 16457150 (2005), 18159056 (2007), 21170264 (2010), 21993507 (2012), … (more) This variant has been reported in hereditary breast/ovarian cancer families in the published literature (PMIDs: 7894493 (1994), 16457150 (2005), 18159056 (2007), 21170264 (2010), 21993507 (2012), 23451180 (2013), 24728189 (2014), 25682074 (2015), and 27062684 (2016)). RNA splicing studies have shown that this variant interferes with BRCA1 mRNA splicing by activating a cryptic splice-site and causing the inclusion of 59 base pairs of intronic sequence in the BRCA1 mRNA (PMIDs: 18424508 (2008), 22505045 (2012), and 23451180 (2013). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Oct 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003810368.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (May 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000292144.4 First in ClinVar: Jul 08, 2016 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 7894493‚ 10923033‚ 18284688‚ 18424508‚ 21993507‚ 22144684‚ 23451180‚ 25452441‚ 33484353‚ 34072659 Comment: This variant causes a T to G nucleotide substitution at the -11 position of intron 4 of the BRCA1 gene. RNA studies have shown that … (more) This variant causes a T to G nucleotide substitution at the -11 position of intron 4 of the BRCA1 gene. RNA studies have shown that this variant causes retention of 59 nucleotides at the 3' end of intron 4 (PMID: 18424508, 23451180). This is expected to create a frameshift and premature translation stop signal, resulting in an absent or non-functional protein product. This variant has been reported to segregate with disease in a large family affected with breast and ovarian cancer (PMID: 7894493), and has been observed in several unrelated individuals affected with breast, ovarian and/or endometrial cancer (PMID: 18284688, 21993507, 25452441, 10923033, 22144684, 33484353, 34072659). This variant has also been identified in 3/250918 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)
Pathogenic (Dec 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004212694.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Oct 02, 2015)	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016) 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: SCV000325254.4 First in ClinVar: Oct 22, 2016 Last updated: Dec 11, 2022
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: SCV000144670.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Observation 1: Number of individuals with the variant: 45 Observation 2: Number of individuals with the variant: 1 Geographic origin: African American Observation 3: Number of individuals with the variant: 1 Geographic origin: Central/Eastern European Observation 4: Number of individuals with the variant: 4 Geographic origin: Western European Observation 5: Number of individuals with the variant: 1 Ethnicity/Population group: African Observation 6: Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Observation 7: Number of individuals with the variant: 3 Ethnicity/Population group: Central/Eastern European Observation 8: Number of individuals with the variant: 1 Ethnicity/Population group: French, English, Western European Observation 9: Number of individuals with the variant: 1 Ethnicity/Population group: Scottish, French Observation 10: Number of individuals with the variant: 50 Ethnicity/Population group: Western European
Pathogenic (Jan 26, 2007)	no assertion criteria provided Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000863669.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018
Pathogenic (Jul 17, 2013)	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: SCV000053624.6 First in ClinVar: Apr 04, 2013 Last updated: Mar 29, 2015
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: SCV000587038.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017
Pathogenic (Dec 01, 1994)	no assertion criteria provided Method: literature only	BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039520.4 First in ClinVar: Apr 04, 2013 Last updated: Jun 17, 2023	Publications: PubMed (1) PubMed: 7894493 Comment on evidence: Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (604370). They … (more) Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (604370). They identified a T-to-G transversion at nucleotide 332 in exon 5 of the BRCA1 gene, leading to a premature termination codon at position 75 and a truncated protein. (less)
Pathogenic (Mar 23, 2024)	no assertion criteria provided Method: clinical testing	BRCA1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005360986.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The BRCA1 c.213-11T>G variant is predicted to interfere with splicing. This variant, which is also known as c.332-11T>G and IVS5-11T>G in the literature, has been … (more) The BRCA1 c.213-11T>G variant is predicted to interfere with splicing. This variant, which is also known as c.332-11T>G and IVS5-11T>G in the literature, has been reported many times in individuals with breast and/or ovarian cancer and in some reports has been shown to segregate with disease in kindreds (see for examples Friedman et al. 1994. PubMed ID: 7894493; Supp. Table 2 in Couch et al. 2015. PubMed ID: 25452441; Table S2 in Azzollini et al. 2016. PubMed ID: 27062684). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), and functional studies using RT-PCR on patient RNA samples have demonstrated the altered splicing empirically (Bonnet et al. 2008. PubMed ID: 18424508). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/37449). Given all the evidence, we too interpret c.213-11T>G as pathogenic. (less)
not provided (-)	no classification provided Method: phenotyping only	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: paternal	GenomeConnect - Brain Gene Registry Accession: SCV002760023.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Comment: Variant interpreted as Pathogenic and reported on 11-14-2018 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided … (more) Variant interpreted as Pathogenic and reported on 11-14-2018 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less) Clinical Features: Global developmental delay (present) , Intellectual disability (present) , Autistic behavior (present) , Speech apraxia (present) , Anxiety (present) Indication for testing: Diagnostic Age: 10-19 years Sex: female Method: Exome Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2018-11-14 Testing laboratory interpretation: Pathogenic
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Comment:

Variant summary: The BRCA1 c.213-11T>G variant affects a conserved intronic nucleotide. 3/5 splice-site tools predict the variant to create a new cryptic splice site and/or weaken the cononical splice site. This in silico predicted result is proven by multiple functional studies showing that this variant leads to a splicing defect, resulting in an extra 59 base pairs at the end of intron 4 and introducing a premature stop codon. This variant was found in 1/121156 control chromosomes at a frequency of 0.0000083, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). However, the variant has been found in multiple HBOC patients or individuals undergoing BRCA1/2 testing as reported in literature and clinical databases. Additionally, several clinical labs and clinical databases have classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic.

Comment:

This sequence change falls in intron 4 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80358061, gnomAD 0.003%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7894493, 10923033, 18284688, 21993507, 22144684, 25452441). It has also been observed to segregate with disease in related individuals. This variant is also known as c.332-11T>G and IVS5-11T>G. ClinVar contains an entry for this variant (Variation ID: 37449). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 18424508, 23451180; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

The BRCA1 c.213-11T>G variant, also known as 332-11T>G or IVS5-11T>G, is reported in the medical literature in multiple individuals and families with breast and/or ovarian cancer (Carter 2018, Friedman 1994, Yost 2019). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37449). This variant is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, in silico analyses and experimental evidence demonstrate this variant causes aberrant intronic splicing (Bonnet 2008, Colombo 2013). Based on available information, this variant is classified as pathogenic. References: Bonnet C et al. Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene. J Med Genet. 2008 Jul;45(7):438-46. PMID: 18424508. Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Colombo M et al. Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. PLoS One. 2013;8(2):e57173. PMID: 23451180. Friedman LS et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet. 1994 Dec;8(4):399-404. PMID: 7894493. Yost S et al. Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers. JNCI Cancer Spectr. 2019 Apr 19;3(2):pkz028. PMID: 31360904.

Comment:

The c.213-11T>G intronic pathogenic mutation results from a T to G substitution eleven nucleotides before coding exon 4 of the BRCA1 gene. In three in vitro studies, this mutation was found to activate a cryptic splice site that leads to the retention of 59 base pairs at the 5' end of coding exon 4, leading to a premature stop codon and a truncated protein product (Colombo M et al. PLoS One. 2013 Mar;8:e57173; Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). In addition, this mutation has been observed in multiple breast and ovarian cancer families to date (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Ellingson MS et al. Breast Cancer Res. Treat. 2015 Sep;153:435-43; Hall MJ et al. Cancer. 2009 May;115:2222-33; John EM et al. JAMA. 2007 Dec;298:2869-76; Musolino A et al. Tumori. 2005 Nov-Dec;91:505-12), including one in which this mutation was reported to segregate with disease through three generations (Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404). Of note, this mutation is also designated as IVS5-11T>G and 75Stop in published literature. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

This pathogenic variant is denoted BRCA1 c.213-11T>G or IVS4-11T>G and consists of a T>G nucleotide substitution at the -11 position of intron 4 of the BRCA1 gene. This variant is also known as BRCA1 332-11T>G or BRCA1 IVS5-11T>G using alternate nomenclature. RNA and minigene assays have demonstrated that BRCA1 c.213-11T>G causes aberrant splicing through activation of a cryptic splice acceptor site, introducing a premature stop codon and leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Bonnet 2008, Colombo 2013). This variant has been observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer, and has been shown to segregate with disease (Friedman 1994, Musolino 2005, John 2007, Colombo 2013, Song 2014, Wong-Brown 2015). We consider this variant to be pathogenic.

Comment:

The c.213-11T>G variant in BRCA1 has been reported in >100 individuals with BRCA 1-associated cancers and has segregated with disease in multiple affected relati ves (Friedman 1994, John 2007, Smith 2012, Wong-Brown 2015, BIC database). This variant has also been reported by multiple clinical laboratories in ClinVar (Var iation ID# 37449). Additionally, this variant has been identified in 3/111540 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org). Sequencing of patient RNA has shown that this variant leads to a retention of 59 base pairs at the 3' end of intron 5, which is predicted to r esult in a premature stop codon (Friedman 1994, Colombo 2013). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individual s with hereditary breast and/or ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the frequency in patients and segregation studies. ACMG/AMP cr iteria applied: PS4, PP1_Strong.

Comment:

This variant has been reported in hereditary breast/ovarian cancer families in the published literature (PMIDs: 7894493 (1994), 16457150 (2005), 18159056 (2007), 21170264 (2010), 21993507 (2012), 23451180 (2013), 24728189 (2014), 25682074 (2015), and 27062684 (2016)). RNA splicing studies have shown that this variant interferes with BRCA1 mRNA splicing by activating a cryptic splice-site and causing the inclusion of 59 base pairs of intronic sequence in the BRCA1 mRNA (PMIDs: 18424508 (2008), 22505045 (2012), and 23451180 (2013). Based on the available information, this variant is classified as pathogenic.

Comment:

This variant causes a T to G nucleotide substitution at the -11 position of intron 4 of the BRCA1 gene. RNA studies have shown that this variant causes retention of 59 nucleotides at the 3' end of intron 4 (PMID: 18424508, 23451180). This is expected to create a frameshift and premature translation stop signal, resulting in an absent or non-functional protein product. This variant has been reported to segregate with disease in a large family affected with breast and ovarian cancer (PMID: 7894493), and has been observed in several unrelated individuals affected with breast, ovarian and/or endometrial cancer (PMID: 18284688, 21993507, 25452441, 10923033, 22144684, 33484353, 34072659). This variant has also been identified in 3/250918 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 c.213-11T>G variant is predicted to interfere with splicing. This variant, which is also known as c.332-11T>G and IVS5-11T>G in the literature, has been reported many times in individuals with breast and/or ovarian cancer and in some reports has been shown to segregate with disease in kindreds (see for examples Friedman et al. 1994. PubMed ID: 7894493; Supp. Table 2 in Couch et al. 2015. PubMed ID: 25452441; Table S2 in Azzollini et al. 2016. PubMed ID: 27062684). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), and functional studies using RT-PCR on patient RNA samples have demonstrated the altered splicing empirically (Bonnet et al. 2008. PubMed ID: 18424508). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/37449). Given all the evidence, we too interpret c.213-11T>G as pathogenic.

Comment:

Variant interpreted as Pathogenic and reported on 11-14-2018 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Study of the Genetic Variants in BRCA1/2 and Non-BRCA Genes in a Population-Based Cohort of 2155 Breast/Ovary Cancer Patients, Including 443 Triple-Negative Breast Cancer Patients, in Argentina.	Solano AR	Cancers	2021	PMID: 34072659
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
Population genetic screening efficiently identifies carriers of autosomal dominant diseases.	Grzymski JJ	Nature medicine	2020	PMID: 32719484
Simultaneous osteosarcoma and renal cell carcinoma with BRCA1 mutation in a young male adult with prior oligodendroglioma.	Dhir A	Pediatric blood & cancer	2020	PMID: 31850619
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: agibbs@bcm.edu	American journal of human genetics	2019	PMID: 31447099
Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers.	Yost S	JNCI cancer spectrum	2019	PMID: 31360904
High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering.	Soussi T	Human mutation	2019	PMID: 30720243
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study.	Azzollini J	European journal of internal medicine	2016	PMID: 27062684
Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy.	Ellingson MS	Breast cancer research and treatment	2015	PMID: 26296701
Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer.	Wong-Brown MW	Breast cancer research and treatment	2015	PMID: 25682074
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.	Couch FJ	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2015	PMID: 25452441
The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population.	Song H	Human molecular genetics	2014	PMID: 24728189
Functional characterization of BRCA1 gene variants by mini-gene splicing assay.	Steffensen AY	European journal of human genetics : EJHG	2014	PMID: 24667779
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
BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group.	Alsop K	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2012	PMID: 22711857
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
Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers.	Finkelman BS	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2012	PMID: 22430266
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
Effects of BRCA1 and BRCA2 mutations on female fertility.	Smith KR	Proceedings. Biological sciences	2012	PMID: 21993507
A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes.	Hondow HL	BMC cancer	2011	PMID: 21702907
Identification of a preneoplastic gene expression profile in tubal epithelium of BRCA1 mutation carriers.	Press JZ	Neoplasia (New York, N.Y.)	2010	PMID: 21170264
BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer.	Hall MJ	Cancer	2009	PMID: 19241424
Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance.	Spearman AD	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2008	PMID: 18824701
Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene.	Bonnet C	Journal of medical genetics	2008	PMID: 18424508
Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients.	Lee E	Breast cancer research : BCR	2008	PMID: 18284688
Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups.	John EM	JAMA	2007	PMID: 18159056
A fluorescent multiplex-DGGE screening test for mutations in the BRCA1 gene.	Kuperstein G	Genetic testing	2006	PMID: 16544996
BRCA1 and BRCA2 mutations in breast and ovarian cancer syndrome: reflection on the Creighton University historical series of high risk families.	Sinilnikova OM	Familial cancer	2006	PMID: 16528604
Molecular profile and clinical variables in BRCA1-positive breast cancers. A population-based study.	Musolino A	Tumori	2005	PMID: 16457150
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.	Judkins T	Cancer research	2005	PMID: 16267036
Comparison of DNA- and RNA-based methods for detection of truncating BRCA1 mutations.	Andrulis IL	Human mutation	2002	PMID: 12112659
The breast cancer information core: database design, structure, and scope.	Szabo C	Human mutation	2000	PMID: 10923033
Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.	Friedman LS	Nature genetics	1994	PMID: 7894493
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Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_007294.4(BRCA1):c.213-11T>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80358061 ...