# NM_007294.4(BRCA1):c.5096G>C (p.Arg1699Pro)

https://sugi.bio/variant/brca1-p-arg1699pro

## Summary

**BRCA1 p.Arg1699Pro (c.5096G>C)** is classified **Uncertain significance** in BRCA1 (ClinVar, Expert panel, 9 submitters; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.9776); Absent from gnomAD v4.1; Associated with BRCA1-related cancer predisposition.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs41293459 · 9 submitters · 5 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BRCA1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 9 submitters, and is linked to BRCA1-related cancer predisposition.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026408/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BRCA1](https://sugi.bio/atlas/gene/BRCA1/) |
| Protein change (HGVS p.) | p.Arg1699Pro |
| Coding change (HGVS c.) | c.5096G>C |
| MANE Select transcript | [NM_007294](https://www.ncbi.nlm.nih.gov/nuccore/NM_007294) |
| dbSNP | [rs41293459](https://www.ncbi.nlm.nih.gov/snp/rs41293459/) |
| Variant type | single nucleotide variant |
| Location | chr17:43063930-43063930 (GRCh38) |
| ClinVar | [VCV55397](https://www.ncbi.nlm.nih.gov/clinvar/variation/55397/) |

**All HGVS expressions:** `LRG_292:g.154054G>C`, `LRG_292t1:c.5096G>C`, `NC_000017.10:g.41215947C>G`, `NC_000017.11:g.43063930C>G`, `NG_005905.2:g.154054G>C`, `NM_001407571.1:c.4883G>C`, `NM_001407581.1:c.5162G>C`, `NM_001407582.1:c.5162G>C`, `NM_001407583.1:c.5159G>C`, `NM_001407585.1:c.5159G>C`, `NM_001407587.1:c.5159G>C`, `NM_001407590.1:c.5156G>C`, `NM_001407591.1:c.5156G>C`, `NM_001407593.1:c.5096G>C`, `NM_001407594.1:c.5096G>C`, `NM_001407596.1:c.5096G>C`, `NM_001407597.1:c.5096G>C`, `NM_001407598.1:c.5096G>C`, `NM_001407602.1:c.5096G>C`, `NM_001407603.1:c.5096G>C`, `NM_001407605.1:c.5096G>C`, `NM_001407610.1:c.5093G>C`, `NM_001407611.1:c.5093G>C`, `NM_001407612.1:c.5093G>C`, `NM_001407613.1:c.5093G>C`, `NM_001407614.1:c.5093G>C`, `NM_001407615.1:c.5093G>C`, `NM_001407616.1:c.5093G>C`, `NM_001407617.1:c.5093G>C`, `NM_001407618.1:c.5093G>C`, `NM_001407619.1:c.5093G>C`, `NM_001407620.1:c.5093G>C`, `NM_001407621.1:c.5093G>C`, `NM_001407622.1:c.5093G>C`, `NM_001407623.1:c.5093G>C`, `NM_001407624.1:c.5093G>C`, `NM_001407625.1:c.5093G>C`, `NM_001407626.1:c.5093G>C`, `NM_001407627.1:c.5090G>C`, `NM_001407628.1:c.5090G>C`, `NM_001407629.1:c.5090G>C`, `NM_001407630.1:c.5090G>C`, `NM_001407631.1:c.5090G>C`, `NM_001407632.1:c.5090G>C`, `NM_001407633.1:c.5090G>C`, `NM_001407634.1:c.5090G>C`, `NM_001407635.1:c.5090G>C`, `NM_001407636.1:c.5090G>C`, `NM_001407637.1:c.5090G>C`, `NM_001407638.1:c.5090G>C`, `NM_001407639.1:c.5090G>C`, `NM_001407640.1:c.5090G>C`, `NM_001407641.1:c.5090G>C`, `NM_001407642.1:c.5090G>C`, `NM_001407644.1:c.5087G>C`, `NM_001407645.1:c.5087G>C`, `NM_001407646.1:c.5084G>C`, `NM_001407647.1:c.5081G>C`, `NM_001407648.1:c.5039G>C`, `NM_001407649.1:c.5036G>C`, `NM_001407653.1:c.5018G>C`, `NM_001407654.1:c.5018G>C`, `NM_001407655.1:c.5018G>C`, `NM_001407656.1:c.5015G>C`, `NM_001407657.1:c.5015G>C`, `NM_001407658.1:c.5015G>C`, `NM_001407659.1:c.5012G>C`, `NM_001407660.1:c.5012G>C`, `NM_001407661.1:c.5012G>C`, `NM_001407662.1:c.5012G>C`, `NM_001407663.1:c.5012G>C`, `NM_001407664.1:c.4973G>C`, `NM_001407665.1:c.4973G>C`, `NM_001407666.1:c.4973G>C`, `NM_001407667.1:c.4973G>C`, `NM_001407668.1:c.4973G>C`, `NM_001407669.1:c.4973G>C`, `NM_001407670.1:c.4970G>C`, `NM_001407671.1:c.4970G>C`, `NM_001407672.1:c.4970G>C`, `NM_001407673.1:c.4970G>C`, `NM_001407674.1:c.4970G>C`, `NM_001407675.1:c.4970G>C`, `NM_001407676.1:c.4970G>C`, `NM_001407677.1:c.4970G>C`, `NM_001407678.1:c.4970G>C`, `NM_001407679.1:c.4970G>C`, `NM_001407680.1:c.4970G>C`, `NM_001407681.1:c.4967G>C`, `NM_001407682.1:c.4967G>C`, `NM_001407683.1:c.4967G>C`, `NM_001407684.1:c.5096G>C`, `NM_001407685.1:c.4967G>C`, `NM_001407686.1:c.4967G>C`, `NM_001407687.1:c.4967G>C`, `NM_001407688.1:c.4967G>C`, `NM_001407689.1:c.4967G>C`, `NM_001407690.1:c.4964G>C`, `NM_001407691.1:c.4964G>C`, `NM_001407692.1:c.4955G>C`, `NM_001407694.1:c.4955G>C`, `NM_001407695.1:c.4955G>C`, `NM_001407696.1:c.4955G>C`, `NM_001407697.1:c.4955G>C`, `NM_001407698.1:c.4955G>C`, `NM_001407724.1:c.4955G>C`, `NM_001407725.1:c.4955G>C`, `NM_001407726.1:c.4955G>C`, `NM_001407727.1:c.4955G>C`, `NM_001407728.1:c.4955G>C`, `NM_001407729.1:c.4955G>C`, `NM_001407730.1:c.4955G>C`, `NM_001407731.1:c.4955G>C`, `NM_001407732.1:c.4952G>C`, `NM_001407733.1:c.4952G>C`, `NM_001407734.1:c.4952G>C`, `NM_001407735.1:c.4952G>C`, `NM_001407736.1:c.4952G>C`, `NM_001407737.1:c.4952G>C`, `NM_001407738.1:c.4952G>C`, `NM_001407739.1:c.4952G>C`, `NM_001407740.1:c.4952G>C`, `NM_001407741.1:c.4952G>C`, `NM_001407742.1:c.4952G>C`, `NM_001407743.1:c.4952G>C`, `NM_001407744.1:c.4952G>C`, `NM_001407745.1:c.4952G>C`, `NM_001407746.1:c.4952G>C`, `NM_001407747.1:c.4952G>C`, `NM_001407748.1:c.4952G>C`, `NM_001407749.1:c.4952G>C`, `NM_001407750.1:c.4952G>C`, `NM_001407751.1:c.4952G>C`, `NM_001407752.1:c.4952G>C`, `NM_001407838.1:c.4949G>C`, `NM_001407839.1:c.4949G>C`, `NM_001407841.1:c.4949G>C`, `NM_001407842.1:c.4949G>C`, `NM_001407843.1:c.4949G>C`, `NM_001407844.1:c.4949G>C`, `NM_001407845.1:c.4949G>C`, `NM_001407846.1:c.4949G>C`, `NM_001407847.1:c.4949G>C`, `NM_001407848.1:c.4949G>C`, `NM_001407849.1:c.4949G>C`, `NM_001407850.1:c.4949G>C`, `NM_001407851.1:c.4949G>C`, `NM_001407852.1:c.4949G>C`, `NM_001407853.1:c.4949G>C`, `NM_001407854.1:c.5096G>C`, `NM_001407858.1:c.5093G>C`, `NM_001407859.1:c.5093G>C`, `NM_001407860.1:c.5093G>C`, `NM_001407861.1:c.5090G>C`, `NM_001407862.1:c.4895G>C`, `NM_001407874.1:c.4889G>C`, `NM_001407875.1:c.4889G>C`, `NM_001407879.1:c.4886G>C`, `NM_001407881.1:c.4886G>C`, `NM_001407882.1:c.4886G>C`, `NM_001407884.1:c.4886G>C`, `NM_001407885.1:c.4886G>C`, `NM_001407886.1:c.4886G>C`, `NM_001407887.1:c.4886G>C`, `NM_001407889.1:c.4886G>C`, `NM_001407894.1:c.4883G>C`, `NM_001407895.1:c.4883G>C`, `NM_001407896.1:c.4883G>C`, `NM_001407897.1:c.4883G>C`, `NM_001407898.1:c.4883G>C`, `NM_001407899.1:c.4883G>C`, `NM_001407900.1:c.4883G>C`, `NM_001407902.1:c.4883G>C`, `NM_001407904.1:c.4883G>C`, `NM_001407906.1:c.4883G>C`, `NM_001407907.1:c.4883G>C`, `NM_001407908.1:c.4883G>C`, `NM_001407909.1:c.4883G>C`, `NM_001407910.1:c.4883G>C`, `NM_001407915.1:c.4880G>C`, `NM_001407916.1:c.4880G>C`, `NM_001407917.1:c.4880G>C`, `NM_001407918.1:c.4880G>C`, `NM_001407919.1:c.4973G>C`, `NM_001407920.1:c.4832G>C`, `NM_001407921.1:c.4832G>C`, `NM_001407922.1:c.4832G>C`, `NM_001407923.1:c.4832G>C`, `NM_001407924.1:c.4832G>C`, `NM_001407925.1:c.4832G>C`, `NM_001407926.1:c.4832G>C`, `NM_001407927.1:c.4829G>C`, `NM_001407928.1:c.4829G>C`, `NM_001407929.1:c.4829G>C`, `NM_001407930.1:c.4829G>C`, `NM_001407931.1:c.4829G>C`, `NM_001407932.1:c.4829G>C`, `NM_001407933.1:c.4829G>C`, `NM_001407934.1:c.4826G>C`, `NM_001407935.1:c.4826G>C`, `NM_001407936.1:c.4826G>C`, `NM_001407937.1:c.4973G>C`, `NM_001407938.1:c.4973G>C`, `NM_001407939.1:c.4970G>C`, `NM_001407940.1:c.4970G>C`, `NM_001407941.1:c.4967G>C`, `NM_001407942.1:c.4955G>C`, `NM_001407943.1:c.4952G>C`, `NM_001407944.1:c.4952G>C`, `NM_001407945.1:c.4952G>C`, `NM_001407946.1:c.4763G>C`, `NM_001407947.1:c.4763G>C`, `NM_001407948.1:c.4763G>C`, `NM_001407949.1:c.4763G>C`, `NM_001407950.1:c.4760G>C`, `NM_001407951.1:c.4760G>C`, `NM_001407952.1:c.4760G>C`, `NM_001407953.1:c.4760G>C`, `NM_001407954.1:c.4760G>C`, `NM_001407955.1:c.4760G>C`, `NM_001407956.1:c.4757G>C`, `NM_001407957.1:c.4757G>C`, `NM_001407958.1:c.4757G>C`, `NM_001407959.1:c.4715G>C`, `NM_001407960.1:c.4712G>C`, `NM_001407962.1:c.4712G>C`, `NM_001407963.1:c.4709G>C`, `NM_001407964.1:c.4634G>C`, `NM_001407965.1:c.4589G>C`, `NM_001407966.1:c.4208G>C`, `NM_001407967.1:c.4205G>C`, `NM_001407968.1:c.2492G>C`, `NM_001407969.1:c.2489G>C`, `NM_001407970.1:c.1853G>C`, `NM_001407971.1:c.1853G>C`, `NM_001407972.1:c.1850G>C`, `NM_001407973.1:c.1787G>C`, `NM_001407974.1:c.1787G>C`, `NM_001407975.1:c.1787G>C`, `NM_001407976.1:c.1787G>C`, `NM_001407977.1:c.1787G>C`, `NM_001407978.1:c.1787G>C`, `NM_001407979.1:c.1784G>C`, `NM_001407980.1:c.1784G>C`, `NM_001407981.1:c.1784G>C`, `NM_001407982.1:c.1784G>C`, `NM_001407983.1:c.1784G>C`, `NM_001407984.1:c.1784G>C`, `NM_001407985.1:c.1784G>C`, `NM_001407986.1:c.1784G>C`, `NM_001407990.1:c.1784G>C`, `NM_001407991.1:c.1784G>C`, `NM_001407992.1:c.1784G>C`, `NM_001407993.1:c.1784G>C`, `NM_001408392.1:c.1781G>C`, `NM_001408396.1:c.1781G>C`, `NM_001408397.1:c.1781G>C`, `NM_001408398.1:c.1781G>C`, `NM_001408399.1:c.1781G>C`, `NM_001408400.1:c.1781G>C`, `NM_001408401.1:c.1781G>C`, `NM_001408402.1:c.1781G>C`, `NM_001408403.1:c.1781G>C`, `NM_001408404.1:c.1781G>C`, `NM_001408406.1:c.1778G>C`, `NM_001408407.1:c.1778G>C`, `NM_001408408.1:c.1778G>C`, `NM_001408409.1:c.1775G>C`, `NM_001408410.1:c.1712G>C`, `NM_001408411.1:c.1709G>C`, `NM_001408412.1:c.1706G>C`, `NM_001408413.1:c.1706G>C`, `NM_001408414.1:c.1706G>C`, `NM_001408415.1:c.1706G>C`, `NM_001408416.1:c.1706G>C`, `NM_001408418.1:c.1670G>C`, `NM_001408419.1:c.1670G>C`, `NM_001408420.1:c.1670G>C`, `NM_001408421.1:c.1667G>C`, `NM_001408422.1:c.1667G>C`, `NM_001408423.1:c.1667G>C`, `NM_001408424.1:c.1667G>C`, `NM_001408425.1:c.1664G>C`, `NM_001408426.1:c.1664G>C`, `NM_001408427.1:c.1664G>C`, `NM_001408428.1:c.1664G>C`, `NM_001408429.1:c.1664G>C`, `NM_001408430.1:c.1664G>C`, `NM_001408431.1:c.1664G>C`, `NM_001408432.1:c.1661G>C`, `NM_001408433.1:c.1661G>C`, `NM_001408434.1:c.1661G>C`, `NM_001408435.1:c.1661G>C`, `NM_001408436.1:c.1661G>C`, `NM_001408437.1:c.1661G>C`, `NM_001408438.1:c.1661G>C`, `NM_001408439.1:c.1661G>C`, `NM_001408440.1:c.1661G>C`, `NM_001408441.1:c.1661G>C`, `NM_001408442.1:c.1661G>C`, `NM_001408443.1:c.1661G>C`, `NM_001408444.1:c.1661G>C`, `NM_001408445.1:c.1658G>C`, `NM_001408446.1:c.1658G>C`, `NM_001408447.1:c.1658G>C`, `NM_001408448.1:c.1658G>C`, `NM_001408450.1:c.1658G>C`, `NM_001408451.1:c.1652G>C`, `NM_001408452.1:c.1646G>C`, `NM_001408453.1:c.1646G>C`, `NM_001408454.1:c.1646G>C`, `NM_001408455.1:c.1646G>C`, `NM_001408456.1:c.1646G>C`, `NM_001408457.1:c.1646G>C`, `NM_001408458.1:c.1643G>C`, `NM_001408459.1:c.1643G>C`, `NM_001408460.1:c.1643G>C`, `NM_001408461.1:c.1643G>C`, `NM_001408462.1:c.1643G>C`, `NM_001408463.1:c.1643G>C`, `NM_001408464.1:c.1643G>C`, `NM_001408465.1:c.1643G>C`, `NM_001408466.1:c.1643G>C`, `NM_001408467.1:c.1643G>C`, `NM_001408468.1:c.1640G>C`, `NM_001408469.1:c.1640G>C`, `NM_001408470.1:c.1640G>C`, `NM_001408472.1:c.1784G>C`, `NM_001408473.1:c.1781G>C`, `NM_001408474.1:c.1586G>C`, `NM_001408475.1:c.1583G>C`, `NM_001408476.1:c.1583G>C`, `NM_001408478.1:c.1577G>C`, `NM_001408479.1:c.1577G>C`, `NM_001408480.1:c.1577G>C`, `NM_001408481.1:c.1574G>C`, `NM_001408482.1:c.1574G>C`, `NM_001408483.1:c.1574G>C`, `NM_001408484.1:c.1574G>C`, `NM_001408485.1:c.1574G>C`, `NM_001408489.1:c.1574G>C`, `NM_001408490.1:c.1574G>C`, `NM_001408491.1:c.1574G>C`, `NM_001408492.1:c.1571G>C`, `NM_001408493.1:c.1571G>C`, `NM_001408494.1:c.1547G>C`, `NM_001408495.1:c.1541G>C`, `NM_001408496.1:c.1523G>C`, `NM_001408497.1:c.1523G>C`, `NM_001408498.1:c.1523G>C`, `NM_001408499.1:c.1523G>C`, `NM_001408500.1:c.1523G>C`, `NM_001408501.1:c.1523G>C`, `NM_001408502.1:c.1520G>C`, `NM_001408503.1:c.1520G>C`, `NM_001408504.1:c.1520G>C`, `NM_001408505.1:c.1517G>C`, `NM_001408506.1:c.1460G>C`, `NM_001408507.1:c.1457G>C`, `NM_001408508.1:c.1448G>C`, `NM_001408509.1:c.1445G>C`, `NM_001408510.1:c.1406G>C`, `NM_001408511.1:c.1403G>C`, `NM_001408512.1:c.1283G>C`, `NM_001408513.1:c.1256G>C`, `NM_001408514.1:c.860G>C`, `NM_007294.4:c.5096G>C`, `NM_007297.4:c.4955G>C`, `NM_007298.4:c.1784G>C`, `NM_007299.4:c.1784G>C`, `NM_007300.4:c.5159G>C`, `NM_007304.2:c.1784G>C`, `NR_027676.2:n.5273G>C`, `U14680.1:n.5215G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9776)
- REVEL 0.843 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -7.813 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 7.634, GERP 2.72, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in BRCA1 (of 11,003 modeled).
- CADD: **PHRED 28.9**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.91** across the covering region of the MANE Select transcript (43,045,681–43,124,096), spanning 78,415 bp. Chi-square p 4.8e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BRCA1** population constraint: LOEUF 0.885, pLI 1.5474e-34, missense-Z 2.3379; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **BRCA1-related cancer predisposition** — Definitive (AD)
- **Fanconi anemia, complementation group S** — Definitive (AR)

## Protein context {#protein}

Residue **1699** lies in the brct 1 domain; a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in bc; pathogenic; strongly reduces affinity for a brip1 phosphopeptide; functionally impaired in vitro); a UniProt-annotated variant site (in bc, oc and fancs; impairs protein stability; functionally impaired in vitro).

AlphaFold model confidence (whole protein): pLDDT 41.99, 11% of residues very-high.

**33 experimental structure(s)** (PDB): [1JM7](https://www.rcsb.org/structure/1JM7), [1JNX](https://www.rcsb.org/structure/1JNX), [1N5O](https://www.rcsb.org/structure/1N5O), [1OQA](https://www.rcsb.org/structure/1OQA), [1T15](https://www.rcsb.org/structure/1T15), [1T29](https://www.rcsb.org/structure/1T29) — incl. mutant structure 1T2U.

## What this gene does {#gene-function}

*Describes the biological roles of BRCA1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BRCA1's established molecular role includes transcription cis-regulatory region binding. p.Arg1699Pro falls in the brct 1 domain. In Reactome, BRCA1 is annotated in disease pathway(s) including **Defective DNA double strand break response due to BARD1 loss of function**, **Defective DNA double strand break response due to BRCA1 loss of function**.

**Disease mechanism (Reactome):** BRCA1 loss or alteration is curated in [Defective DNA double strand break response due to BARD1 loss of function](https://reactome.org/content/detail/R-HSA-9699150), [Defective DNA double strand break response due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9663199), [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331).

### Pathways affected {#pathways}

BRCA1 participates in **28 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective DNA double strand break response due to BARD1 loss of function](https://reactome.org/content/detail/R-HSA-9699150) | curated |
| ⚕ [Defective DNA double strand break response due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9663199) | curated |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | curated |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646) | curated |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | curated |
| ⚕ [Impaired BRCA2 binding to PALB2](https://reactome.org/content/detail/R-HSA-9709603) | curated |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | curated |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | curated |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | curated |
| [Metalloprotease DUBs](https://reactome.org/content/detail/R-HSA-5689901) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Negative Regulation of DNA Double Strand Break Response](https://reactome.org/content/detail/R-HSA-9974237) | curated |
| [Nonhomologous End-Joining (NHEJ)](https://reactome.org/content/detail/R-HSA-5693571) | curated |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | curated |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | curated |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |
| [Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence](https://reactome.org/content/detail/R-HSA-9825895) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | curated |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [Transcriptional Regulation by E2F6](https://reactome.org/content/detail/R-HSA-8953750) | curated |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | electronic |
| [Meiotic synapsis](https://reactome.org/content/detail/R-HSA-1221632) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription cis-regulatory region binding, p53 binding, transcription coactivator activity, RNA binding, ubiquitin-protein transferase activity, enzyme binding.

**Biological process:** double-strand break repair via homologous recombination, DNA damage tolerance, double-strand break repair, regulation of transcription by RNA polymerase II, chromosome segregation, mitotic G2 DNA damage checkpoint signaling.

## Clinical significance {#significance}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-08-25.

**Submitter consensus:** conflicting (4 Likely pathogenic, 3 Uncertain significance, 1 Uncertain Significance).

**Submission history:** 9 submissions (2010–2025); classifications have differed over time.

**ClinGen expert panel:** Uncertain Significance — ENIGMA BRCA1 and BRCA2 VCEP (BRCA1-related cancer predisposition). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PP3`.
*Considered but not met:* `PS3`, `BS3`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.5096G>C variant in BRCA1 is a missense variant predicted to cause substitution of Arginine by Proline at amino acid 1699 (p.(Arg1699Pro)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by three calibrated studies with discordant results. Functional effect similar to benign control variants (PMID:38709234) and to pathogenic control variants (PMID:30209399, 35196514) (PS3 and BS3 not met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.43, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.01 predicts no impact on splicing (score threshold <0.10) (PP3 met). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50087 · approved 2025-08-25 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/de958936-79e3-46c2-963c-cc255b445281).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-06-28 |
| Baylor Genetics | Uncertain significance | flagged submission | clinical testing | 2023-07-01 |
| Institute of Human Genetics, University of Leipzig Medical Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-09 |
| Brotman Baty Institute, University of Washington |  | no classification provided | in vitro |  |
| ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen | Uncertain Significance | reviewed by expert panel | curation | 2025-08-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-04-27 |
| Breast Cancer Information Core (BIC) (BRCA1) | Uncertain significance | no assertion criteria provided | clinical testing | 2010-12-17 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-10-19 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-13 |

## Associated conditions {#conditions}

[BRCA1-related cancer predisposition](https://sugi.bio/atlas/disease/brca1-related-cancer-predisposition/), [hereditary breast ovarian cancer syndrome](https://sugi.bio/atlas/disease/hereditary-breast-ovarian-cancer-syndrome/), [breast-ovarian cancer, familial, susceptibility to, 1](https://sugi.bio/atlas/disease/breast-ovarian-cancer-familial-susceptibility-to-1/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/).

**Reported phenotype names (ClinVar):** BRCA1-related cancer predisposition, Breast-ovarian cancer, familial, susceptibility to, 1, Hereditary breast ovarian cancer syndrome, Hereditary cancer-predisposing syndrome, Familial cancer of breast, Hereditary breast and/or ovarian cancer syndrome, Hereditary breast and ovarian cancer syndrome, Hereditary breast and ovarian cancer, Breast and ovarian cancer, BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.

## Same-residue context {#hotspot}

Residue **1699** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [BRCA1 p.Arg1699Gln](/variant/brca1-p-arg1699gln), [BRCA1 p.Arg1699Trp](/variant/brca1-p-arg1699trp), [BRCA1 p.Arg1699Leu](/variant/brca1-p-arg1699leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRCA1 variant pages (same residue, condition, or type): [BRCA1 p.Arg1699Gln](/variant/brca1-p-arg1699gln), [BRCA1 p.Arg1699Trp](/variant/brca1-p-arg1699trp), [BRCA1 p.Arg1699Leu](/variant/brca1-p-arg1699leu), [BRCA1 p.Arg1699=](/variant/brca1-p-arg1699), [BRCA1 c.134+3A>T](/variant/brca1-c-134-plus-3a-t), [BRCA1 c.135-1G>T](/variant/brca1-c-135-minus-1g-t), [BRCA1 c.212+1G>A](/variant/brca1-c-212-plus-1g-a), [BRCA1 c.212+1G>T](/variant/brca1-c-212-plus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 55397). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*