# NM_007294.4(BRCA1):c.181T>G (p.Cys61Gly)

https://sugi.bio/variant/brca1-p-cys61gly

## Summary

**BRCA1 p.Cys61Gly (c.181T>G)** is classified **Pathogenic** in BRCA1 (ClinVar, Expert panel, 69 submitters; last evaluated 2015-08-10). AlphaMissense: likely pathogenic (0.9904); Very rare (popmax 0.00239%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

**At a glance:** Pathogenic · review: Expert panel · rsID rs28897672 · 69 submitters · 10 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00239%, nfe)

## For patients & families {#patients}

This is a change in the BRCA1 gene that is considered disease-causing, submitted by 69 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.Cys61Gly |
| Coding change (HGVS c.) | c.181T>G |
| MANE Select transcript | [NM_007294](https://www.ncbi.nlm.nih.gov/nuccore/NM_007294) |
| dbSNP | [rs28897672](https://www.ncbi.nlm.nih.gov/snp/rs28897672/) |
| Variant type | single nucleotide variant |
| Location | chr17:43106487-43106487 (GRCh38) |
| ClinVar | [VCV17661](https://www.ncbi.nlm.nih.gov/clinvar/variation/17661/) |

**All HGVS expressions:** `LRG_292:g.111497T>G`, `LRG_292t1:c.181T>G`, `NC_000017.10:g.41258504A>C`, `NC_000017.11:g.43106487A>C`, `NG_005905.2:g.111497T>G`, `NM_001407571.1:c.-8T>G`, `NM_001407581.1:c.181T>G`, `NM_001407582.1:c.181T>G`, `NM_001407583.1:c.181T>G`, `NM_001407585.1:c.181T>G`, `NM_001407587.1:c.181T>G`, `NM_001407590.1:c.181T>G`, `NM_001407591.1:c.181T>G`, `NM_001407593.1:c.181T>G`, `NM_001407594.1:c.181T>G`, `NM_001407596.1:c.181T>G`, `NM_001407597.1:c.181T>G`, `NM_001407598.1:c.181T>G`, `NM_001407602.1:c.181T>G`, `NM_001407603.1:c.181T>G`, `NM_001407605.1:c.181T>G`, `NM_001407610.1:c.181T>G`, `NM_001407611.1:c.181T>G`, `NM_001407612.1:c.181T>G`, `NM_001407613.1:c.181T>G`, `NM_001407614.1:c.181T>G`, `NM_001407615.1:c.181T>G`, `NM_001407616.1:c.181T>G`, `NM_001407617.1:c.181T>G`, `NM_001407618.1:c.181T>G`, `NM_001407619.1:c.181T>G`, `NM_001407620.1:c.181T>G`, `NM_001407621.1:c.181T>G`, `NM_001407622.1:c.181T>G`, `NM_001407623.1:c.181T>G`, `NM_001407624.1:c.181T>G`, `NM_001407625.1:c.181T>G`, `NM_001407626.1:c.181T>G`, `NM_001407627.1:c.181T>G`, `NM_001407628.1:c.181T>G`, `NM_001407629.1:c.181T>G`, `NM_001407630.1:c.181T>G`, `NM_001407631.1:c.181T>G`, `NM_001407632.1:c.181T>G`, `NM_001407633.1:c.181T>G`, `NM_001407634.1:c.181T>G`, `NM_001407635.1:c.181T>G`, `NM_001407636.1:c.181T>G`, `NM_001407637.1:c.181T>G`, `NM_001407638.1:c.181T>G`, `NM_001407639.1:c.181T>G`, `NM_001407640.1:c.181T>G`, `NM_001407641.1:c.181T>G`, `NM_001407642.1:c.181T>G`, `NM_001407644.1:c.181T>G`, `NM_001407645.1:c.181T>G`, `NM_001407646.1:c.181T>G`, `NM_001407647.1:c.181T>G`, `NM_001407648.1:c.181T>G`, `NM_001407649.1:c.181T>G`, `NM_001407652.1:c.181T>G`, `NM_001407664.1:c.181T>G`, `NM_001407665.1:c.181T>G`, `NM_001407666.1:c.181T>G`, `NM_001407667.1:c.181T>G`, `NM_001407668.1:c.181T>G`, `NM_001407669.1:c.181T>G`, `NM_001407670.1:c.181T>G`, `NM_001407671.1:c.181T>G`, `NM_001407672.1:c.181T>G`, `NM_001407673.1:c.181T>G`, `NM_001407674.1:c.181T>G`, `NM_001407675.1:c.181T>G`, `NM_001407676.1:c.181T>G`, `NM_001407677.1:c.181T>G`, `NM_001407678.1:c.181T>G`, `NM_001407679.1:c.181T>G`, `NM_001407680.1:c.181T>G`, `NM_001407681.1:c.181T>G`, `NM_001407682.1:c.181T>G`, `NM_001407683.1:c.181T>G`, `NM_001407684.1:c.181T>G`, `NM_001407685.1:c.181T>G`, `NM_001407686.1:c.181T>G`, `NM_001407687.1:c.181T>G`, `NM_001407688.1:c.181T>G`, `NM_001407689.1:c.181T>G`, `NM_001407690.1:c.181T>G`, `NM_001407691.1:c.181T>G`, `NM_001407692.1:c.40T>G`, `NM_001407694.1:c.40T>G`, `NM_001407695.1:c.40T>G`, `NM_001407696.1:c.40T>G`, `NM_001407697.1:c.40T>G`, `NM_001407698.1:c.40T>G`, `NM_001407724.1:c.40T>G`, `NM_001407725.1:c.40T>G`, `NM_001407726.1:c.40T>G`, `NM_001407727.1:c.40T>G`, `NM_001407728.1:c.40T>G`, `NM_001407729.1:c.40T>G`, `NM_001407730.1:c.40T>G`, `NM_001407731.1:c.40T>G`, `NM_001407732.1:c.40T>G`, `NM_001407733.1:c.40T>G`, `NM_001407734.1:c.40T>G`, `NM_001407735.1:c.40T>G`, `NM_001407736.1:c.40T>G`, `NM_001407737.1:c.40T>G`, `NM_001407738.1:c.40T>G`, `NM_001407739.1:c.40T>G`, `NM_001407740.1:c.40T>G`, `NM_001407741.1:c.40T>G`, `NM_001407742.1:c.40T>G`, `NM_001407743.1:c.40T>G`, `NM_001407744.1:c.40T>G`, `NM_001407745.1:c.40T>G`, `NM_001407746.1:c.40T>G`, `NM_001407747.1:c.40T>G`, `NM_001407748.1:c.40T>G`, `NM_001407749.1:c.40T>G`, `NM_001407750.1:c.40T>G`, `NM_001407751.1:c.40T>G`, `NM_001407752.1:c.40T>G`, `NM_001407838.1:c.40T>G`, `NM_001407839.1:c.40T>G`, `NM_001407841.1:c.40T>G`, `NM_001407842.1:c.40T>G`, `NM_001407843.1:c.40T>G`, `NM_001407844.1:c.40T>G`, `NM_001407845.1:c.40T>G`, `NM_001407846.1:c.40T>G`, `NM_001407847.1:c.40T>G`, `NM_001407848.1:c.40T>G`, `NM_001407849.1:c.40T>G`, `NM_001407850.1:c.40T>G`, `NM_001407851.1:c.40T>G`, `NM_001407852.1:c.40T>G`, `NM_001407853.1:c.-8T>G`, `NM_001407854.1:c.181T>G`, `NM_001407858.1:c.181T>G`, `NM_001407859.1:c.181T>G`, `NM_001407860.1:c.181T>G`, `NM_001407861.1:c.181T>G`, `NM_001407863.1:c.181T>G`, `NM_001407879.1:c.-8T>G`, `NM_001407881.1:c.-8T>G`, `NM_001407882.1:c.-8T>G`, `NM_001407884.1:c.-8T>G`, `NM_001407885.1:c.-8T>G`, `NM_001407886.1:c.-8T>G`, `NM_001407887.1:c.-8T>G`, `NM_001407889.1:c.-8T>G`, `NM_001407894.1:c.-8T>G`, `NM_001407895.1:c.-8T>G`, `NM_001407896.1:c.-8T>G`, `NM_001407897.1:c.-8T>G`, `NM_001407898.1:c.-8T>G`, `NM_001407899.1:c.-8T>G`, `NM_001407900.1:c.-8T>G`, `NM_001407902.1:c.-8T>G`, `NM_001407904.1:c.-8T>G`, `NM_001407906.1:c.-8T>G`, `NM_001407907.1:c.-8T>G`, `NM_001407908.1:c.-8T>G`, `NM_001407909.1:c.-8T>G`, `NM_001407910.1:c.-8T>G`, `NM_001407915.1:c.-8T>G`, `NM_001407916.1:c.-8T>G`, `NM_001407917.1:c.-8T>G`, `NM_001407918.1:c.-8T>G`, `NM_001407919.1:c.181T>G`, `NM_001407920.1:c.40T>G`, `NM_001407921.1:c.40T>G`, `NM_001407922.1:c.40T>G`, `NM_001407923.1:c.40T>G`, `NM_001407924.1:c.40T>G`, `NM_001407925.1:c.40T>G`, `NM_001407926.1:c.40T>G`, `NM_001407927.1:c.40T>G`, `NM_001407928.1:c.40T>G`, `NM_001407929.1:c.40T>G`, `NM_001407930.1:c.40T>G`, `NM_001407931.1:c.40T>G`, `NM_001407932.1:c.40T>G`, `NM_001407933.1:c.40T>G`, `NM_001407934.1:c.40T>G`, `NM_001407935.1:c.40T>G`, `NM_001407936.1:c.40T>G`, `NM_001407937.1:c.181T>G`, `NM_001407938.1:c.181T>G`, `NM_001407939.1:c.181T>G`, `NM_001407940.1:c.181T>G`, `NM_001407941.1:c.181T>G`, `NM_001407942.1:c.40T>G`, `NM_001407943.1:c.40T>G`, `NM_001407944.1:c.40T>G`, `NM_001407945.1:c.40T>G`, `NM_001407946.1:c.-8T>G`, `NM_001407947.1:c.-8T>G`, `NM_001407948.1:c.-8T>G`, `NM_001407949.1:c.-8T>G`, `NM_001407950.1:c.-8T>G`, `NM_001407951.1:c.-8T>G`, `NM_001407952.1:c.-8T>G`, `NM_001407953.1:c.-8T>G`, `NM_001407954.1:c.-8T>G`, `NM_001407955.1:c.-8T>G`, `NM_001407956.1:c.-8T>G`, `NM_001407957.1:c.-8T>G`, `NM_001407958.1:c.-8T>G`, `NM_001407964.1:c.40T>G`, `NM_001407968.1:c.181T>G`, `NM_001407969.1:c.181T>G`, `NM_001407970.1:c.181T>G`, `NM_001407971.1:c.181T>G`, `NM_001407972.1:c.181T>G`, `NM_001407973.1:c.181T>G`, `NM_001407974.1:c.181T>G`, `NM_001407975.1:c.181T>G`, `NM_001407976.1:c.181T>G`, `NM_001407977.1:c.181T>G`, `NM_001407978.1:c.181T>G`, `NM_001407979.1:c.181T>G`, `NM_001407980.1:c.181T>G`, `NM_001407981.1:c.181T>G`, `NM_001407982.1:c.181T>G`, `NM_001407983.1:c.181T>G`, `NM_001407984.1:c.181T>G`, `NM_001407985.1:c.181T>G`, `NM_001407986.1:c.181T>G`, `NM_001407990.1:c.181T>G`, `NM_001407991.1:c.181T>G`, `NM_001407992.1:c.181T>G`, `NM_001407993.1:c.181T>G`, `NM_001408392.1:c.181T>G`, `NM_001408396.1:c.181T>G`, `NM_001408397.1:c.181T>G`, `NM_001408398.1:c.181T>G`, `NM_001408399.1:c.181T>G`, `NM_001408400.1:c.181T>G`, `NM_001408401.1:c.181T>G`, `NM_001408402.1:c.181T>G`, `NM_001408403.1:c.181T>G`, `NM_001408404.1:c.181T>G`, `NM_001408406.1:c.181T>G`, `NM_001408407.1:c.181T>G`, `NM_001408408.1:c.181T>G`, `NM_001408410.1:c.40T>G`, `NM_001408418.1:c.181T>G`, `NM_001408419.1:c.181T>G`, `NM_001408420.1:c.181T>G`, `NM_001408421.1:c.181T>G`, `NM_001408422.1:c.181T>G`, `NM_001408423.1:c.181T>G`, `NM_001408424.1:c.181T>G`, `NM_001408425.1:c.181T>G`, `NM_001408426.1:c.181T>G`, `NM_001408427.1:c.181T>G`, `NM_001408428.1:c.181T>G`, `NM_001408429.1:c.181T>G`, `NM_001408430.1:c.181T>G`, `NM_001408431.1:c.181T>G`, `NM_001408432.1:c.181T>G`, `NM_001408433.1:c.181T>G`, `NM_001408434.1:c.181T>G`, `NM_001408435.1:c.181T>G`, `NM_001408436.1:c.181T>G`, `NM_001408437.1:c.181T>G`, `NM_001408438.1:c.181T>G`, `NM_001408439.1:c.181T>G`, `NM_001408440.1:c.181T>G`, `NM_001408441.1:c.181T>G`, `NM_001408442.1:c.181T>G`, `NM_001408443.1:c.181T>G`, `NM_001408444.1:c.181T>G`, `NM_001408445.1:c.181T>G`, `NM_001408446.1:c.181T>G`, `NM_001408447.1:c.181T>G`, `NM_001408448.1:c.181T>G`, `NM_001408450.1:c.181T>G`, `NM_001408452.1:c.40T>G`, `NM_001408453.1:c.40T>G`, `NM_001408454.1:c.40T>G`, `NM_001408455.1:c.40T>G`, `NM_001408456.1:c.40T>G`, `NM_001408457.1:c.40T>G`, `NM_001408458.1:c.40T>G`, `NM_001408459.1:c.40T>G`, `NM_001408460.1:c.40T>G`, `NM_001408461.1:c.40T>G`, `NM_001408462.1:c.40T>G`, `NM_001408463.1:c.40T>G`, `NM_001408464.1:c.40T>G`, `NM_001408465.1:c.40T>G`, `NM_001408466.1:c.40T>G`, `NM_001408467.1:c.40T>G`, `NM_001408468.1:c.40T>G`, `NM_001408469.1:c.40T>G`, `NM_001408470.1:c.40T>G`, `NM_001408472.1:c.181T>G`, `NM_001408473.1:c.181T>G`, `NM_001408478.1:c.-8T>G`, `NM_001408479.1:c.-8T>G`, `NM_001408480.1:c.-8T>G`, `NM_001408481.1:c.-8T>G`, `NM_001408482.1:c.-8T>G`, `NM_001408483.1:c.-8T>G`, `NM_001408484.1:c.-8T>G`, `NM_001408485.1:c.-8T>G`, `NM_001408489.1:c.-8T>G`, `NM_001408490.1:c.-8T>G`, `NM_001408491.1:c.-8T>G`, `NM_001408492.1:c.-8T>G`, `NM_001408493.1:c.-8T>G`, `NM_001408494.1:c.181T>G`, `NM_001408495.1:c.181T>G`, `NM_001408496.1:c.40T>G`, `NM_001408497.1:c.40T>G`, `NM_001408498.1:c.40T>G`, `NM_001408499.1:c.40T>G`, `NM_001408500.1:c.40T>G`, `NM_001408501.1:c.40T>G`, `NM_001408502.1:c.-8T>G`, `NM_001408503.1:c.40T>G`, `NM_001408504.1:c.40T>G`, `NM_001408505.1:c.40T>G`, `NM_001408506.1:c.-8T>G`, `NM_001408507.1:c.-8T>G`, `NM_001408508.1:c.-8T>G`, `NM_001408509.1:c.-8T>G`, `NM_001408511.1:c.40T>G`, `NM_001408513.1:c.-8T>G`, `NM_001408514.1:c.-8T>G`, `NM_007294.4:c.181T>G`, `NM_007297.4:c.40T>G`, `NM_007298.4:c.181T>G`, `NM_007299.4:c.181T>G`, `NM_007300.4:c.181T>G`, `NM_007304.2:c.181T>G`, `NR_027676.2:n.383T>G`, `U14680.1:n.300T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9904) — concordant with the pathogenic call
- REVEL 0.948 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.214 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.169, GERP 2.43, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in BRCA1 (of 11,003 modeled).
- CADD: **PHRED 24.5**. 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 **0.00239%** (nfe) · FAF95 0.00166% · FAF99 0.00143% · 28/1,172,588 in the highest group · 30/1,604,818 alleles overall — very rare (popmax 0.00239%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00239% | 41,878 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,106 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,978 |

*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 3/3, triplosensitivity 0/3. *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 **61** lies in a UniProt-annotated variant site (in bc and oc; pathogenic; no interaction with bap1).

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 2015-08-10.

**Submitter consensus:** conflicting (69 Pathogenic, 2 pathogenic, 2 not provided, 1 Likely pathogenic).

**Submission history:** 75 submissions (2000–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical and Functional Genomics Group, A.C.Camargo Cancer Center | Pathogenic | criteria provided, single submitter | research |  |
| Department of Medical Genetics, Oslo University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2015-07-01 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2000-06-01 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Pathogenic | no assertion criteria provided | clinical testing |  |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-24 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-21 |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Pathogenic | criteria provided, single submitter | clinical testing | 2020-10-23 |
| Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-04 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-22 |
| Institute of Human Genetics, University of Leipzig Medical Center | pathogenic | criteria provided, single submitter | clinical testing | 2025-11-24 |
| Institute of Human Genetics, University of Leipzig Medical Center | pathogenic | criteria provided, single submitter | clinical testing | 2026-06-29 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-23 |
| Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Pathogenic | reviewed by expert panel | curation | 2015-08-10 |
| Breast Cancer Information Core (BIC) (BRCA1) | not provided | no classification provided | clinical testing |  |
| Molecular Genetics Laboratory, University of Michigan | Pathogenic | criteria provided, single submitter | clinical testing | 2014-11-03 |
| Sharing Clinical Reports Project (SCRP) | Pathogenic | no assertion criteria provided | clinical testing | 2013-09-18 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2017-02-23 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2017-08-24 |
| Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2017-05-25 |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2019-05-28 |
| GeneKor MSA | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-01 |
| Institute of Genomics, University of Tartu | Pathogenic | criteria provided, single submitter | research |  |
| Clinical Genetics and Genomics, Karolinska University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2014-06-13 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Pathogenic | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| Genetic Services Laboratory, University of Chicago | Pathogenic | no assertion criteria provided | clinical testing | 2021-02-05 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-10 |
| Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-03 |
| Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-27 |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-04 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-30 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-22 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-09 |
| MGZ Medical Genetics Center | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-13 |
| Diagnostics Centre, Carl Von Ossietzky University Oldenburg | Pathogenic | no assertion criteria provided | clinical testing | 2023-10-16 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-10 |
| Laboratory of Genetics, Children's Clinical University Hospital Latvia | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-16 |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-02-03 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2026-03-01 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Pathogenic | criteria provided, single submitter | clinical testing | 2026-07-06 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Pathogenic | no assertion criteria provided | clinical testing | 2016-04-06 |
| Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Pathogenic | no assertion criteria provided | research | 2014-01-31 |
| Department of Pathology and Molecular Medicine, Queen's University | Pathogenic | criteria provided, single submitter | clinical testing | 2017-04-20 |
| Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Pathogenic | criteria provided, single submitter | clinical testing | 2017-07-12 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Pathogenic | no assertion criteria provided | clinical testing |  |
| German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Pathogenic | no assertion criteria provided | research | 2018-12-01 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2019-01-31 |
| CZECANCA consortium | Pathogenic | no assertion criteria provided | clinical testing | 2019-06-11 |
| Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Pathogenic | criteria provided, single submitter | clinical testing | 2020-04-02 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Pathogenic | no assertion criteria provided | clinical testing |  |
| Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | Pathogenic | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Pathogenic | no assertion criteria provided | clinical testing |  |
| National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-16 |
| Sema4, Sema4 | Pathogenic | criteria provided, single submitter | curation | 2021-12-10 |
| BRCAlab, Lund University | Pathogenic | no assertion criteria provided | clinical testing | 2022-08-26 |
| Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Pathogenic | criteria provided, single submitter | clinical testing | 2015-10-02 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Pathogenic | criteria provided, single submitter | research | 2022-12-09 |
| Medical Genetics, Medical University Pleven | Pathogenic | no assertion criteria provided | research |  |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-03 |
| All of Us Research Program, National Institutes of Health | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-29 |
| German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Pathogenic | criteria provided, single submitter | curation | 2024-11-11 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2015-05-13 |
| GenomeConnect - Invitae Patient Insights Network | not provided | no classification provided | phenotyping only |  |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-11 |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2015-11-12 |
| Brotman Baty Institute, University of Washington |  | no classification provided | in vitro |  |
| University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM) | Pathogenic | criteria provided, single submitter | clinical testing |  |
| NHS Central & South Genomic Laboratory Hub | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-25 |
| Department of Genomics, ADN Uruguay | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-27 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-29 |
| Helix | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-25 |
| Genesis Genomics | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-29 |

## 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/), [breast carcinoma](https://sugi.bio/atlas/disease/breast-carcinoma/), [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/), [ovarian neoplasm](https://sugi.bio/atlas/disease/ovarian-neoplasm/), [breast neoplasm](https://sugi.bio/atlas/disease/breast-neoplasm/), [Fanconi anemia, complementation group S](https://sugi.bio/atlas/disease/fanconi-anemia-complementation-group-s/), [BRCA1-related cancer predisposition](https://sugi.bio/atlas/disease/brca1-related-cancer-predisposition/).

**Reported phenotype names (ClinVar):** Breast-ovarian cancer, familial, susceptibility to, 1, Hereditary breast ovarian cancer syndrome, Hereditary cancer-predisposing syndrome, not provided, Familial cancer of breast, Breast carcinoma, Breast neoplasm, Ovarian neoplasm, Breast and/or ovarian cancer, BRCA1-related cancer predisposition.

## Same-residue context {#hotspot}

Residue **61** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [BRCA1 p.Cys61fs](/variant/brca1-p-cys61fs), [BRCA1 p.Cys61Ser](/variant/brca1-p-cys61ser), [BRCA1 p.Cys61Arg](/variant/brca1-p-cys61arg), [BRCA1 p.Cys61Tyr](/variant/brca1-p-cys61tyr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Functional evidence (MaveDB) {#mavedb}

Measured in **1 multiplexed functional assay** (deep mutational scanning):

| Assay (MaveDB score set) | Raw score | License |
| --- | --- | --- |
| [BRCA1 RING domain variant effect map](https://www.mavedb.org/score-sets/urn:mavedb:00000002-a-1/) | -3.020 | CC BY-NC-SA 4.0 |
*Raw per-assay scores — sign and scale differ between assays; interpret within each score set. Experimental functional evidence (an ACMG PS3/BS3 input), not a classification.*

## Similar variants {#similar}

Related BRCA1 variant pages (same residue, condition, or type): [BRCA1 p.Cys61Arg](/variant/brca1-p-cys61arg), [BRCA1 p.Cys61Ser](/variant/brca1-p-cys61ser), [BRCA1 p.Cys61Tyr](/variant/brca1-p-cys61tyr), [BRCA1 p.Cys61=](/variant/brca1-p-cys61), [BRCA1 p.Cys61Phe](/variant/brca1-p-cys61phe), [BRCA1 p.Cys61fs](/variant/brca1-p-cys61fs), [BRCA1 c.134+3A>T](/variant/brca1-c-134-plus-3a-t), [BRCA1 c.135-1G>T](/variant/brca1-c-135-minus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 17661). 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.*