# NM_007294.4(BRCA1):c.544T>A (p.Leu182Met)

https://sugi.bio/variant/brca1-p-leu182met

## Summary

**BRCA1 p.Leu182Met (c.544T>A)** is classified **Uncertain significance** in BRCA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.208); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1060502339 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · 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 2 submitters, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/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.Leu182Met |
| Coding change (HGVS c.) | c.544T>A |
| MANE Select transcript | [NM_007294](https://www.ncbi.nlm.nih.gov/nuccore/NM_007294) |
| dbSNP | [rs1060502339](https://www.ncbi.nlm.nih.gov/snp/rs1060502339/) |
| Variant type | single nucleotide variant |
| Location | chr17:43099778-43099778 (GRCh38) |
| ClinVar | [VCV409323](https://www.ncbi.nlm.nih.gov/clinvar/variation/409323/) |

**All HGVS expressions:** `LRG_292:g.118206T>A`, `LRG_292t1:c.544T>A`, `NC_000017.10:g.41251795A>T`, `NC_000017.11:g.43099778A>T`, `NG_005905.2:g.118206T>A`, `NM_001407571.1:c.331T>A`, `NM_001407581.1:c.544T>A`, `NM_001407582.1:c.544T>A`, `NM_001407583.1:c.544T>A`, `NM_001407585.1:c.544T>A`, `NM_001407587.1:c.541T>A`, `NM_001407590.1:c.541T>A`, `NM_001407591.1:c.541T>A`, `NM_001407593.1:c.544T>A`, `NM_001407594.1:c.544T>A`, `NM_001407596.1:c.544T>A`, `NM_001407597.1:c.544T>A`, `NM_001407598.1:c.544T>A`, `NM_001407602.1:c.544T>A`, `NM_001407603.1:c.544T>A`, `NM_001407605.1:c.544T>A`, `NM_001407610.1:c.541T>A`, `NM_001407611.1:c.541T>A`, `NM_001407612.1:c.541T>A`, `NM_001407613.1:c.541T>A`, `NM_001407614.1:c.541T>A`, `NM_001407615.1:c.541T>A`, `NM_001407616.1:c.544T>A`, `NM_001407617.1:c.544T>A`, `NM_001407618.1:c.544T>A`, `NM_001407619.1:c.544T>A`, `NM_001407620.1:c.544T>A`, `NM_001407621.1:c.544T>A`, `NM_001407622.1:c.544T>A`, `NM_001407623.1:c.544T>A`, `NM_001407624.1:c.544T>A`, `NM_001407625.1:c.544T>A`, `NM_001407626.1:c.544T>A`, `NM_001407627.1:c.541T>A`, `NM_001407628.1:c.541T>A`, `NM_001407629.1:c.541T>A`, `NM_001407630.1:c.541T>A`, `NM_001407631.1:c.541T>A`, `NM_001407632.1:c.541T>A`, `NM_001407633.1:c.541T>A`, `NM_001407634.1:c.541T>A`, `NM_001407635.1:c.541T>A`, `NM_001407636.1:c.541T>A`, `NM_001407637.1:c.541T>A`, `NM_001407638.1:c.541T>A`, `NM_001407639.1:c.544T>A`, `NM_001407640.1:c.544T>A`, `NM_001407641.1:c.544T>A`, `NM_001407642.1:c.544T>A`, `NM_001407644.1:c.541T>A`, `NM_001407645.1:c.541T>A`, `NM_001407646.1:c.535T>A`, `NM_001407647.1:c.535T>A`, `NM_001407648.1:c.544T>A`, `NM_001407649.1:c.541T>A`, `NM_001407652.1:c.544T>A`, `NM_001407653.1:c.466T>A`, `NM_001407654.1:c.466T>A`, `NM_001407655.1:c.466T>A`, `NM_001407656.1:c.466T>A`, `NM_001407657.1:c.466T>A`, `NM_001407658.1:c.466T>A`, `NM_001407659.1:c.463T>A`, `NM_001407660.1:c.463T>A`, `NM_001407661.1:c.463T>A`, `NM_001407662.1:c.463T>A`, `NM_001407663.1:c.466T>A`, `NM_001407664.1:c.544T>A`, `NM_001407665.1:c.544T>A`, `NM_001407666.1:c.544T>A`, `NM_001407667.1:c.544T>A`, `NM_001407668.1:c.544T>A`, `NM_001407669.1:c.544T>A`, `NM_001407670.1:c.541T>A`, `NM_001407671.1:c.541T>A`, `NM_001407672.1:c.541T>A`, `NM_001407673.1:c.541T>A`, `NM_001407674.1:c.544T>A`, `NM_001407675.1:c.544T>A`, `NM_001407676.1:c.544T>A`, `NM_001407677.1:c.544T>A`, `NM_001407678.1:c.544T>A`, `NM_001407679.1:c.544T>A`, `NM_001407680.1:c.544T>A`, `NM_001407681.1:c.544T>A`, `NM_001407682.1:c.544T>A`, `NM_001407683.1:c.544T>A`, `NM_001407684.1:c.544T>A`, `NM_001407685.1:c.541T>A`, `NM_001407686.1:c.541T>A`, `NM_001407687.1:c.541T>A`, `NM_001407688.1:c.541T>A`, `NM_001407689.1:c.541T>A`, `NM_001407690.1:c.541T>A`, `NM_001407691.1:c.541T>A`, `NM_001407692.1:c.403T>A`, `NM_001407694.1:c.403T>A`, `NM_001407695.1:c.403T>A`, `NM_001407696.1:c.403T>A`, `NM_001407697.1:c.403T>A`, `NM_001407698.1:c.403T>A`, `NM_001407724.1:c.403T>A`, `NM_001407725.1:c.403T>A`, `NM_001407726.1:c.403T>A`, `NM_001407727.1:c.403T>A`, `NM_001407728.1:c.403T>A`, `NM_001407729.1:c.403T>A`, `NM_001407730.1:c.403T>A`, `NM_001407731.1:c.403T>A`, `NM_001407732.1:c.403T>A`, `NM_001407733.1:c.403T>A`, `NM_001407734.1:c.403T>A`, `NM_001407735.1:c.403T>A`, `NM_001407736.1:c.403T>A`, `NM_001407737.1:c.403T>A`, `NM_001407738.1:c.403T>A`, `NM_001407739.1:c.403T>A`, `NM_001407740.1:c.400T>A`, `NM_001407741.1:c.400T>A`, `NM_001407742.1:c.400T>A`, `NM_001407743.1:c.400T>A`, `NM_001407744.1:c.400T>A`, `NM_001407745.1:c.400T>A`, `NM_001407746.1:c.400T>A`, `NM_001407747.1:c.400T>A`, `NM_001407748.1:c.400T>A`, `NM_001407749.1:c.400T>A`, `NM_001407750.1:c.403T>A`, `NM_001407751.1:c.403T>A`, `NM_001407752.1:c.403T>A`, `NM_001407838.1:c.400T>A`, `NM_001407839.1:c.400T>A`, `NM_001407841.1:c.400T>A`, `NM_001407842.1:c.400T>A`, `NM_001407843.1:c.400T>A`, `NM_001407844.1:c.400T>A`, `NM_001407845.1:c.400T>A`, `NM_001407846.1:c.400T>A`, `NM_001407847.1:c.400T>A`, `NM_001407848.1:c.400T>A`, `NM_001407849.1:c.400T>A`, `NM_001407850.1:c.403T>A`, `NM_001407851.1:c.403T>A`, `NM_001407852.1:c.403T>A`, `NM_001407853.1:c.331T>A`, `NM_001407854.1:c.544T>A`, `NM_001407858.1:c.544T>A`, `NM_001407859.1:c.544T>A`, `NM_001407860.1:c.541T>A`, `NM_001407861.1:c.541T>A`, `NM_001407862.1:c.466T>A`, `NM_001407863.1:c.544T>A`, `NM_001407874.1:c.463T>A`, `NM_001407875.1:c.463T>A`, `NM_001407879.1:c.334T>A`, `NM_001407881.1:c.334T>A`, `NM_001407882.1:c.334T>A`, `NM_001407884.1:c.334T>A`, `NM_001407885.1:c.334T>A`, `NM_001407886.1:c.334T>A`, `NM_001407887.1:c.334T>A`, `NM_001407889.1:c.334T>A`, `NM_001407894.1:c.331T>A`, `NM_001407895.1:c.331T>A`, `NM_001407896.1:c.331T>A`, `NM_001407897.1:c.331T>A`, `NM_001407898.1:c.331T>A`, `NM_001407899.1:c.331T>A`, `NM_001407900.1:c.334T>A`, `NM_001407902.1:c.334T>A`, `NM_001407904.1:c.334T>A`, `NM_001407906.1:c.334T>A`, `NM_001407907.1:c.334T>A`, `NM_001407908.1:c.334T>A`, `NM_001407909.1:c.334T>A`, `NM_001407910.1:c.334T>A`, `NM_001407915.1:c.331T>A`, `NM_001407916.1:c.331T>A`, `NM_001407917.1:c.331T>A`, `NM_001407918.1:c.331T>A`, `NM_001407919.1:c.544T>A`, `NM_001407920.1:c.403T>A`, `NM_001407921.1:c.403T>A`, `NM_001407922.1:c.403T>A`, `NM_001407923.1:c.403T>A`, `NM_001407924.1:c.403T>A`, `NM_001407925.1:c.403T>A`, `NM_001407926.1:c.403T>A`, `NM_001407927.1:c.403T>A`, `NM_001407928.1:c.403T>A`, `NM_001407929.1:c.403T>A`, `NM_001407930.1:c.400T>A`, `NM_001407931.1:c.400T>A`, `NM_001407932.1:c.400T>A`, `NM_001407933.1:c.403T>A`, `NM_001407934.1:c.400T>A`, `NM_001407935.1:c.403T>A`, `NM_001407936.1:c.400T>A`, `NM_001407937.1:c.544T>A`, `NM_001407938.1:c.544T>A`, `NM_001407939.1:c.544T>A`, `NM_001407940.1:c.541T>A`, `NM_001407941.1:c.541T>A`, `NM_001407942.1:c.403T>A`, `NM_001407943.1:c.400T>A`, `NM_001407944.1:c.403T>A`, `NM_001407945.1:c.403T>A`, `NM_001407946.1:c.334T>A`, `NM_001407947.1:c.334T>A`, `NM_001407948.1:c.334T>A`, `NM_001407949.1:c.334T>A`, `NM_001407950.1:c.334T>A`, `NM_001407951.1:c.334T>A`, `NM_001407952.1:c.334T>A`, `NM_001407953.1:c.334T>A`, `NM_001407954.1:c.331T>A`, `NM_001407955.1:c.331T>A`, `NM_001407956.1:c.331T>A`, `NM_001407957.1:c.334T>A`, `NM_001407958.1:c.331T>A`, `NM_001407959.1:c.163T>A`, `NM_001407960.1:c.163T>A`, `NM_001407962.1:c.160T>A`, `NM_001407963.1:c.163T>A`, `NM_001407964.1:c.400T>A`, `NM_001407965.1:c.163T>A`, `NM_001407968.1:c.544T>A`, `NM_001407969.1:c.544T>A`, `NM_001407970.1:c.544T>A`, `NM_001407971.1:c.544T>A`, `NM_001407972.1:c.541T>A`, `NM_001407973.1:c.544T>A`, `NM_001407974.1:c.544T>A`, `NM_001407975.1:c.544T>A`, `NM_001407976.1:c.544T>A`, `NM_001407977.1:c.544T>A`, `NM_001407978.1:c.544T>A`, `NM_001407979.1:c.544T>A`, `NM_001407980.1:c.544T>A`, `NM_001407981.1:c.544T>A`, `NM_001407982.1:c.544T>A`, `NM_001407983.1:c.544T>A`, `NM_001407984.1:c.541T>A`, `NM_001407985.1:c.541T>A`, `NM_001407986.1:c.541T>A`, `NM_001407990.1:c.544T>A`, `NM_001407991.1:c.541T>A`, `NM_001407992.1:c.541T>A`, `NM_001407993.1:c.544T>A`, `NM_001408392.1:c.541T>A`, `NM_001408396.1:c.541T>A`, `NM_001408397.1:c.541T>A`, `NM_001408398.1:c.541T>A`, `NM_001408399.1:c.541T>A`, `NM_001408400.1:c.541T>A`, `NM_001408401.1:c.541T>A`, `NM_001408402.1:c.541T>A`, `NM_001408403.1:c.544T>A`, `NM_001408404.1:c.544T>A`, `NM_001408406.1:c.544T>A`, `NM_001408407.1:c.541T>A`, `NM_001408408.1:c.535T>A`, `NM_001408409.1:c.466T>A`, `NM_001408410.1:c.403T>A`, `NM_001408411.1:c.466T>A`, `NM_001408412.1:c.466T>A`, `NM_001408413.1:c.463T>A`, `NM_001408414.1:c.466T>A`, `NM_001408415.1:c.466T>A`, `NM_001408416.1:c.463T>A`, `NM_001408418.1:c.544T>A`, `NM_001408419.1:c.544T>A`, `NM_001408420.1:c.544T>A`, `NM_001408421.1:c.541T>A`, `NM_001408422.1:c.544T>A`, `NM_001408423.1:c.544T>A`, `NM_001408424.1:c.541T>A`, `NM_001408425.1:c.544T>A`, `NM_001408426.1:c.544T>A`, `NM_001408427.1:c.544T>A`, `NM_001408428.1:c.544T>A`, `NM_001408429.1:c.544T>A`, `NM_001408430.1:c.544T>A`, `NM_001408431.1:c.541T>A`, `NM_001408432.1:c.541T>A`, `NM_001408433.1:c.541T>A`, `NM_001408434.1:c.541T>A`, `NM_001408435.1:c.541T>A`, `NM_001408436.1:c.544T>A`, `NM_001408437.1:c.544T>A`, `NM_001408438.1:c.544T>A`, `NM_001408439.1:c.544T>A`, `NM_001408440.1:c.544T>A`, `NM_001408441.1:c.544T>A`, `NM_001408442.1:c.544T>A`, `NM_001408443.1:c.544T>A`, `NM_001408444.1:c.544T>A`, `NM_001408445.1:c.541T>A`, `NM_001408446.1:c.541T>A`, `NM_001408447.1:c.541T>A`, `NM_001408448.1:c.541T>A`, `NM_001408450.1:c.541T>A`, `NM_001408451.1:c.409T>A`, `NM_001408452.1:c.403T>A`, `NM_001408453.1:c.403T>A`, `NM_001408454.1:c.403T>A`, `NM_001408455.1:c.403T>A`, `NM_001408456.1:c.403T>A`, `NM_001408457.1:c.403T>A`, `NM_001408458.1:c.403T>A`, `NM_001408459.1:c.403T>A`, `NM_001408460.1:c.403T>A`, `NM_001408461.1:c.403T>A`, `NM_001408462.1:c.400T>A`, `NM_001408463.1:c.400T>A`, `NM_001408464.1:c.400T>A`, `NM_001408465.1:c.400T>A`, `NM_001408466.1:c.403T>A`, `NM_001408467.1:c.403T>A`, `NM_001408468.1:c.400T>A`, `NM_001408469.1:c.403T>A`, `NM_001408470.1:c.400T>A`, `NM_001408472.1:c.544T>A`, `NM_001408473.1:c.541T>A`, `NM_001408474.1:c.466T>A`, `NM_001408475.1:c.463T>A`, `NM_001408476.1:c.466T>A`, `NM_001408478.1:c.334T>A`, `NM_001408479.1:c.334T>A`, `NM_001408480.1:c.334T>A`, `NM_001408481.1:c.334T>A`, `NM_001408482.1:c.334T>A`, `NM_001408483.1:c.334T>A`, `NM_001408484.1:c.334T>A`, `NM_001408485.1:c.334T>A`, `NM_001408489.1:c.334T>A`, `NM_001408490.1:c.331T>A`, `NM_001408491.1:c.331T>A`, `NM_001408492.1:c.334T>A`, `NM_001408493.1:c.331T>A`, `NM_001408494.1:c.544T>A`, `NM_001408495.1:c.541T>A`, `NM_001408496.1:c.403T>A`, `NM_001408497.1:c.403T>A`, `NM_001408498.1:c.403T>A`, `NM_001408499.1:c.403T>A`, `NM_001408500.1:c.403T>A`, `NM_001408501.1:c.403T>A`, `NM_001408502.1:c.334T>A`, `NM_001408503.1:c.400T>A`, `NM_001408504.1:c.400T>A`, `NM_001408505.1:c.400T>A`, `NM_001408506.1:c.334T>A`, `NM_001408507.1:c.334T>A`, `NM_001408508.1:c.331T>A`, `NM_001408509.1:c.331T>A`, `NM_001408510.1:c.163T>A`, `NM_001408511.1:c.400T>A`, `NM_001408512.1:c.163T>A`, `NM_001408513.1:c.334T>A`, `NM_001408514.1:c.334T>A`, `NM_007294.4:c.544T>A`, `NM_007297.4:c.403T>A`, `NM_007298.4:c.544T>A`, `NM_007299.4:c.544T>A`, `NM_007300.4:c.544T>A`, `NM_007304.2:c.544T>A`, `NR_027676.2:n.721T>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.208)
- REVEL 0.501 (indeterminate)
- SaProt LLR -8.547 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 0.699, GERP -5.22, phastCons 0.007 — weakly conserved position
- CADD: **PHRED 16.09**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.34 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- 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}


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. 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-10.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2016–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-04-24 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [hereditary breast ovarian cancer syndrome](https://sugi.bio/atlas/disease/hereditary-breast-ovarian-cancer-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Hereditary breast ovarian cancer syndrome, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer, Hereditary breast and ovarian cancer syndrome (HBOC), Hereditary breast and ovarian cancer, Hereditary breast and ovarian cancer syndrome.

## Similar variants {#similar}

Related BRCA1 variant pages (same residue, condition, or type): [BRCA1 p.Leu182Phe](/variant/brca1-p-leu182phe), [BRCA1 p.Leu182=](/variant/brca1-p-leu182), [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), [BRCA1 c.212+3A>G](/variant/brca1-c-212-plus-3a-g), [BRCA1 c.213-12A>G](/variant/brca1-c-213-minus-12a-g).

### 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 409323). 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.*