# NM_007294.4(BRCA1):c.131G>T (p.Cys44Phe)

https://sugi.bio/variant/brca1-p-cys44phe

## Summary

**BRCA1 p.Cys44Phe (c.131G>T)** is classified **Pathogenic** in BRCA1 (ClinVar, Expert panel, 28 submitters; last evaluated 2019-06-18). AlphaMissense: likely pathogenic (0.9946); Ultra-rare (popmax 0.0165%, mid); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

**At a glance:** Pathogenic · review: Expert panel · rsID rs80357446 · 28 submitters · 6 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the BRCA1 gene that is considered disease-causing, submitted by 28 submitters, and is linked to breast-ovarian cancer, familial, susceptibility to, 1.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult, Elderly |
| Diagnostic panels | BRCA1 is a diagnostic-grade gene on 25 Genomics England panels |

**Commonly reported features of Hereditary breast and/or ovarian cancer syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the fallopian tube — Very frequent (99-80%)
- Primary peritoneal carcinoma — Very frequent (99-80%)
- Ovarian neoplasm — Very frequent (99-80%)
- Breast carcinoma — Frequent (79-30%)
- Melanoma — Occasional (29-5%)
- Neoplasm of the pancreas — Occasional (29-5%)
- Prostate cancer — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027801/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.Cys44Phe |
| Coding change (HGVS c.) | c.131G>T |
| MANE Select transcript | [NM_007294](https://www.ncbi.nlm.nih.gov/nuccore/NM_007294) |
| dbSNP | [rs80357446](https://www.ncbi.nlm.nih.gov/snp/rs80357446/) |
| Variant type | single nucleotide variant |
| Location | chr17:43115729-43115729 (GRCh38) |
| ClinVar | [VCV54200](https://www.ncbi.nlm.nih.gov/clinvar/variation/54200/) |

**All HGVS expressions:** `LRG_292:g.102255G>T`, `LRG_292t1:c.131G>T`, `NC_000017.10:g.41267746C>A`, `NC_000017.11:g.43115729C>A`, `NG_005905.2:g.102255G>T`, `NM_001407571.1:c.-58G>T`, `NM_001407581.1:c.131G>T`, `NM_001407582.1:c.131G>T`, `NM_001407583.1:c.131G>T`, `NM_001407585.1:c.131G>T`, `NM_001407587.1:c.131G>T`, `NM_001407590.1:c.131G>T`, `NM_001407591.1:c.131G>T`, `NM_001407593.1:c.131G>T`, `NM_001407594.1:c.131G>T`, `NM_001407596.1:c.131G>T`, `NM_001407597.1:c.131G>T`, `NM_001407598.1:c.131G>T`, `NM_001407602.1:c.131G>T`, `NM_001407603.1:c.131G>T`, `NM_001407605.1:c.131G>T`, `NM_001407610.1:c.131G>T`, `NM_001407611.1:c.131G>T`, `NM_001407612.1:c.131G>T`, `NM_001407613.1:c.131G>T`, `NM_001407614.1:c.131G>T`, `NM_001407615.1:c.131G>T`, `NM_001407616.1:c.131G>T`, `NM_001407617.1:c.131G>T`, `NM_001407618.1:c.131G>T`, `NM_001407619.1:c.131G>T`, `NM_001407620.1:c.131G>T`, `NM_001407621.1:c.131G>T`, `NM_001407622.1:c.131G>T`, `NM_001407623.1:c.131G>T`, `NM_001407624.1:c.131G>T`, `NM_001407625.1:c.131G>T`, `NM_001407626.1:c.131G>T`, `NM_001407627.1:c.131G>T`, `NM_001407628.1:c.131G>T`, `NM_001407629.1:c.131G>T`, `NM_001407630.1:c.131G>T`, `NM_001407631.1:c.131G>T`, `NM_001407632.1:c.131G>T`, `NM_001407633.1:c.131G>T`, `NM_001407634.1:c.131G>T`, `NM_001407635.1:c.131G>T`, `NM_001407636.1:c.131G>T`, `NM_001407637.1:c.131G>T`, `NM_001407638.1:c.131G>T`, `NM_001407639.1:c.131G>T`, `NM_001407640.1:c.131G>T`, `NM_001407641.1:c.131G>T`, `NM_001407642.1:c.131G>T`, `NM_001407644.1:c.131G>T`, `NM_001407645.1:c.131G>T`, `NM_001407646.1:c.131G>T`, `NM_001407647.1:c.131G>T`, `NM_001407648.1:c.131G>T`, `NM_001407649.1:c.131G>T`, `NM_001407652.1:c.131G>T`, `NM_001407653.1:c.131G>T`, `NM_001407654.1:c.131G>T`, `NM_001407655.1:c.131G>T`, `NM_001407656.1:c.131G>T`, `NM_001407657.1:c.131G>T`, `NM_001407658.1:c.131G>T`, `NM_001407659.1:c.131G>T`, `NM_001407660.1:c.131G>T`, `NM_001407661.1:c.131G>T`, `NM_001407662.1:c.131G>T`, `NM_001407663.1:c.131G>T`, `NM_001407664.1:c.131G>T`, `NM_001407665.1:c.131G>T`, `NM_001407666.1:c.131G>T`, `NM_001407667.1:c.131G>T`, `NM_001407668.1:c.131G>T`, `NM_001407669.1:c.131G>T`, `NM_001407670.1:c.131G>T`, `NM_001407671.1:c.131G>T`, `NM_001407672.1:c.131G>T`, `NM_001407673.1:c.131G>T`, `NM_001407674.1:c.131G>T`, `NM_001407675.1:c.131G>T`, `NM_001407676.1:c.131G>T`, `NM_001407677.1:c.131G>T`, `NM_001407678.1:c.131G>T`, `NM_001407679.1:c.131G>T`, `NM_001407680.1:c.131G>T`, `NM_001407681.1:c.131G>T`, `NM_001407682.1:c.131G>T`, `NM_001407683.1:c.131G>T`, `NM_001407684.1:c.131G>T`, `NM_001407685.1:c.131G>T`, `NM_001407686.1:c.131G>T`, `NM_001407687.1:c.131G>T`, `NM_001407688.1:c.131G>T`, `NM_001407689.1:c.131G>T`, `NM_001407690.1:c.131G>T`, `NM_001407691.1:c.131G>T`, `NM_001407694.1:c.-127G>T`, `NM_001407695.1:c.-131G>T`, `NM_001407696.1:c.-127G>T`, `NM_001407697.1:c.-11G>T`, `NM_001407724.1:c.-127G>T`, `NM_001407725.1:c.-11G>T`, `NM_001407727.1:c.-127G>T`, `NM_001407728.1:c.-11G>T`, `NM_001407729.1:c.-11G>T`, `NM_001407730.1:c.-11G>T`, `NM_001407731.1:c.-127G>T`, `NM_001407733.1:c.-127G>T`, `NM_001407734.1:c.-11G>T`, `NM_001407735.1:c.-11G>T`, `NM_001407737.1:c.-11G>T`, `NM_001407739.1:c.-11G>T`, `NM_001407740.1:c.-11G>T`, `NM_001407741.1:c.-11G>T`, `NM_001407743.1:c.-11G>T`, `NM_001407745.1:c.-11G>T`, `NM_001407746.1:c.-127G>T`, `NM_001407748.1:c.-11G>T`, `NM_001407749.1:c.-127G>T`, `NM_001407752.1:c.-11G>T`, `NM_001407838.1:c.-11G>T`, `NM_001407839.1:c.-11G>T`, `NM_001407842.1:c.-127G>T`, `NM_001407843.1:c.-127G>T`, `NM_001407844.1:c.-11G>T`, `NM_001407846.1:c.-11G>T`, `NM_001407847.1:c.-11G>T`, `NM_001407848.1:c.-11G>T`, `NM_001407850.1:c.-11G>T`, `NM_001407851.1:c.-11G>T`, `NM_001407853.1:c.-58G>T`, `NM_001407854.1:c.131G>T`, `NM_001407858.1:c.131G>T`, `NM_001407859.1:c.131G>T`, `NM_001407860.1:c.131G>T`, `NM_001407861.1:c.131G>T`, `NM_001407862.1:c.131G>T`, `NM_001407863.1:c.131G>T`, `NM_001407874.1:c.131G>T`, `NM_001407875.1:c.131G>T`, `NM_001407879.1:c.-58G>T`, `NM_001407882.1:c.-58G>T`, `NM_001407884.1:c.-58G>T`, `NM_001407885.1:c.-58G>T`, `NM_001407886.1:c.-58G>T`, `NM_001407887.1:c.-58G>T`, `NM_001407889.1:c.-174G>T`, `NM_001407894.1:c.-58G>T`, `NM_001407895.1:c.-58G>T`, `NM_001407896.1:c.-58G>T`, `NM_001407897.1:c.-58G>T`, `NM_001407899.1:c.-58G>T`, `NM_001407900.1:c.-174G>T`, `NM_001407904.1:c.-58G>T`, `NM_001407906.1:c.-58G>T`, `NM_001407907.1:c.-58G>T`, `NM_001407908.1:c.-58G>T`, `NM_001407909.1:c.-58G>T`, `NM_001407910.1:c.-58G>T`, `NM_001407915.1:c.-58G>T`, `NM_001407916.1:c.-58G>T`, `NM_001407917.1:c.-58G>T`, `NM_001407918.1:c.-58G>T`, `NM_001407919.1:c.131G>T`, `NM_001407920.1:c.-11G>T`, `NM_001407921.1:c.-11G>T`, `NM_001407922.1:c.-11G>T`, `NM_001407923.1:c.-11G>T`, `NM_001407926.1:c.-11G>T`, `NM_001407927.1:c.-11G>T`, `NM_001407930.1:c.-127G>T`, `NM_001407933.1:c.-11G>T`, `NM_001407934.1:c.-11G>T`, `NM_001407935.1:c.-11G>T`, `NM_001407937.1:c.131G>T`, `NM_001407938.1:c.131G>T`, `NM_001407939.1:c.131G>T`, `NM_001407940.1:c.131G>T`, `NM_001407941.1:c.131G>T`, `NM_001407942.1:c.-127G>T`, `NM_001407943.1:c.-11G>T`, `NM_001407944.1:c.-11G>T`, `NM_001407946.1:c.-58G>T`, `NM_001407947.1:c.-58G>T`, `NM_001407948.1:c.-58G>T`, `NM_001407949.1:c.-58G>T`, `NM_001407950.1:c.-58G>T`, `NM_001407951.1:c.-58G>T`, `NM_001407952.1:c.-58G>T`, `NM_001407953.1:c.-58G>T`, `NM_001407954.1:c.-58G>T`, `NM_001407955.1:c.-58G>T`, `NM_001407956.1:c.-58G>T`, `NM_001407957.1:c.-58G>T`, `NM_001407958.1:c.-58G>T`, `NM_001407960.1:c.-173G>T`, `NM_001407962.1:c.-173G>T`, `NM_001407964.1:c.-11G>T`, `NM_001407965.1:c.-289G>T`, `NM_001407968.1:c.131G>T`, `NM_001407969.1:c.131G>T`, `NM_001407970.1:c.131G>T`, `NM_001407971.1:c.131G>T`, `NM_001407972.1:c.131G>T`, `NM_001407973.1:c.131G>T`, `NM_001407974.1:c.131G>T`, `NM_001407975.1:c.131G>T`, `NM_001407976.1:c.131G>T`, `NM_001407977.1:c.131G>T`, `NM_001407978.1:c.131G>T`, `NM_001407979.1:c.131G>T`, `NM_001407980.1:c.131G>T`, `NM_001407981.1:c.131G>T`, `NM_001407982.1:c.131G>T`, `NM_001407983.1:c.131G>T`, `NM_001407984.1:c.131G>T`, `NM_001407985.1:c.131G>T`, `NM_001407986.1:c.131G>T`, `NM_001407990.1:c.131G>T`, `NM_001407991.1:c.131G>T`, `NM_001407992.1:c.131G>T`, `NM_001407993.1:c.131G>T`, `NM_001408392.1:c.131G>T`, `NM_001408396.1:c.131G>T`, `NM_001408397.1:c.131G>T`, `NM_001408398.1:c.131G>T`, `NM_001408399.1:c.131G>T`, `NM_001408400.1:c.131G>T`, `NM_001408401.1:c.131G>T`, `NM_001408402.1:c.131G>T`, `NM_001408403.1:c.131G>T`, `NM_001408404.1:c.131G>T`, `NM_001408406.1:c.131G>T`, `NM_001408407.1:c.131G>T`, `NM_001408408.1:c.131G>T`, `NM_001408409.1:c.131G>T`, `NM_001408410.1:c.-11G>T`, `NM_001408411.1:c.131G>T`, `NM_001408412.1:c.131G>T`, `NM_001408413.1:c.131G>T`, `NM_001408414.1:c.131G>T`, `NM_001408415.1:c.131G>T`, `NM_001408416.1:c.131G>T`, `NM_001408418.1:c.131G>T`, `NM_001408419.1:c.131G>T`, `NM_001408420.1:c.131G>T`, `NM_001408421.1:c.131G>T`, `NM_001408422.1:c.131G>T`, `NM_001408423.1:c.131G>T`, `NM_001408424.1:c.131G>T`, `NM_001408425.1:c.131G>T`, `NM_001408426.1:c.131G>T`, `NM_001408427.1:c.131G>T`, `NM_001408428.1:c.131G>T`, `NM_001408429.1:c.131G>T`, `NM_001408430.1:c.131G>T`, `NM_001408431.1:c.131G>T`, `NM_001408432.1:c.131G>T`, `NM_001408433.1:c.131G>T`, `NM_001408434.1:c.131G>T`, `NM_001408435.1:c.131G>T`, `NM_001408436.1:c.131G>T`, `NM_001408437.1:c.131G>T`, `NM_001408438.1:c.131G>T`, `NM_001408439.1:c.131G>T`, `NM_001408440.1:c.131G>T`, `NM_001408441.1:c.131G>T`, `NM_001408442.1:c.131G>T`, `NM_001408443.1:c.131G>T`, `NM_001408444.1:c.131G>T`, `NM_001408445.1:c.131G>T`, `NM_001408446.1:c.131G>T`, `NM_001408447.1:c.131G>T`, `NM_001408448.1:c.131G>T`, `NM_001408450.1:c.131G>T`, `NM_001408452.1:c.-11G>T`, `NM_001408453.1:c.-11G>T`, `NM_001408455.1:c.-127G>T`, `NM_001408456.1:c.-127G>T`, `NM_001408458.1:c.-11G>T`, `NM_001408462.1:c.-11G>T`, `NM_001408463.1:c.-11G>T`, `NM_001408465.1:c.-131G>T`, `NM_001408466.1:c.-11G>T`, `NM_001408468.1:c.-127G>T`, `NM_001408469.1:c.-11G>T`, `NM_001408470.1:c.-11G>T`, `NM_001408472.1:c.131G>T`, `NM_001408473.1:c.131G>T`, `NM_001408474.1:c.131G>T`, `NM_001408475.1:c.131G>T`, `NM_001408476.1:c.131G>T`, `NM_001408478.1:c.-58G>T`, `NM_001408479.1:c.-58G>T`, `NM_001408480.1:c.-58G>T`, `NM_001408481.1:c.-58G>T`, `NM_001408482.1:c.-58G>T`, `NM_001408483.1:c.-58G>T`, `NM_001408484.1:c.-58G>T`, `NM_001408485.1:c.-58G>T`, `NM_001408489.1:c.-58G>T`, `NM_001408490.1:c.-58G>T`, `NM_001408491.1:c.-58G>T`, `NM_001408492.1:c.-174G>T`, `NM_001408493.1:c.-58G>T`, `NM_001408494.1:c.131G>T`, `NM_001408495.1:c.131G>T`, `NM_001408497.1:c.-11G>T`, `NM_001408499.1:c.-11G>T`, `NM_001408500.1:c.-11G>T`, `NM_001408501.1:c.-127G>T`, `NM_001408502.1:c.-58G>T`, `NM_001408503.1:c.-11G>T`, `NM_001408504.1:c.-11G>T`, `NM_001408505.1:c.-11G>T`, `NM_001408506.1:c.-58G>T`, `NM_001408507.1:c.-58G>T`, `NM_001408508.1:c.-58G>T`, `NM_001408509.1:c.-58G>T`, `NM_001408510.1:c.-173G>T`, `NM_001408512.1:c.-173G>T`, `NM_001408513.1:c.-58G>T`, `NM_001408514.1:c.-58G>T`, `NM_007294.4:c.131G>T`, `NM_007297.4:c.-8+8288G>T`, `NM_007298.4:c.131G>T`, `NM_007299.4:c.131G>T`, `NM_007300.3:c.131G>T`, `NM_007300.4:c.131G>T`, `NM_007304.2:c.131G>T`, `NR_027676.2:n.333G>T`, `U14680.1:n.250G>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9946) — concordant with the pathogenic call
- REVEL 0.933 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.136 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.6, GERP 1.76, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in BRCA1 (of 11,003 modeled).
- CADD: **PHRED 27.9**. 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 (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/6,062 in the highest group · 3/1,461,168 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| European (non-Finnish) | 0.00017% | 589,831 |

*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}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2019-06-18.

**Submitter consensus:** conflicting (24 Pathogenic, 1 Likely pathogenic, 1 Uncertain significance, 1 pathogenic).

**Submission history:** 28 submissions (2004–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Likely pathogenic | no assertion criteria provided | research | 2015-12-17 |
| Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Pathogenic | no assertion criteria provided | clinical testing | 2011-11-10 |
| GeneKor MSA | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-01 |
| Clinical Genetics and Genomics, Karolinska University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2014-11-18 |
| Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-03 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-06-06 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-22 |
| Sharing Clinical Reports Project (SCRP) | Pathogenic | no assertion criteria provided | clinical testing | 2012-08-07 |
| Molecular Genetics Laboratory, University of Michigan | Pathogenic | criteria provided, single submitter | clinical testing | 2016-04-21 |
| Breast Cancer Information Core (BIC) (BRCA1) | Uncertain significance | no assertion criteria provided | clinical testing | 2004-02-20 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2018-10-31 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2018-03-07 |
| BRCAlab, Lund University | Pathogenic | no assertion criteria provided | clinical testing | 2022-08-26 |
| Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Pathogenic | reviewed by expert panel | curation | 2019-06-18 |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-17 |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-17 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-21 |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Pathogenic | no assertion criteria provided | clinical testing | 2023-05-05 |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2017-02-01 |
| Brotman Baty Institute, University of Washington |  | no classification provided | in vitro |  |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2022-12-14 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | pathogenic | criteria provided, single submitter | clinical testing | 2025-08-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-26 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-26 |
| Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Pathogenic | criteria provided, single submitter | clinical testing | 2015-10-02 |
| All of Us Research Program, National Institutes of Health | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-08 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Pathogenic | criteria provided, single submitter | clinical testing | 2016-08-30 |
| Molecular Pathology, Peter Maccallum Cancer Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-06 |

## Associated conditions {#conditions}

[breast-ovarian cancer, familial, susceptibility to, 1](https://sugi.bio/atlas/disease/breast-ovarian-cancer-familial-susceptibility-to-1/), [hereditary breast ovarian cancer syndrome](https://sugi.bio/atlas/disease/hereditary-breast-ovarian-cancer-syndrome/), [pancreatic cancer, susceptibility to, 4](https://sugi.bio/atlas/disease/pancreatic-cancer-susceptibility-to-4/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/), [Fanconi anemia, complementation group S](https://sugi.bio/atlas/disease/fanconi-anemia-complementation-group-s/).

**Reported phenotype names (ClinVar):** Breast-ovarian cancer, familial, susceptibility to, 1, Hereditary cancer-predisposing syndrome, not provided, Hereditary breast ovarian cancer syndrome, Breast and/or ovarian cancer, Familial cancer of breast, Fanconi anemia, complementation group S, Pancreatic cancer, susceptibility to, 4, BREAST CANCER, FAMILIAL, Hereditary breast cancer.

## Same-residue context {#hotspot}

Residue **44** carries **6 other pathogenic ClinVar variants** — a recurrently-mutated position: [BRCA1 p.Cys44=](/variant/brca1-p-cys44), [BRCA1 p.Cys44Ser](/variant/brca1-p-cys44ser), [BRCA1 p.Cys44Arg](/variant/brca1-p-cys44arg), [BRCA1 p.Cys44fs](/variant/brca1-p-cys44fs), [BRCA1 p.Cys44Tyr](/variant/brca1-p-cys44tyr), [BRCA1 p.Cys44Trp](/variant/brca1-p-cys44trp). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRCA1 variant pages (same residue, condition, or type): [BRCA1 p.Cys44=](/variant/brca1-p-cys44), [BRCA1 p.Cys44Tyr](/variant/brca1-p-cys44tyr), [BRCA1 p.Cys44Arg](/variant/brca1-p-cys44arg), [BRCA1 p.Cys44Trp](/variant/brca1-p-cys44trp), [BRCA1 p.Cys44fs](/variant/brca1-p-cys44fs), [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).

### 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 54200). 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.*