# NM_007294.4(BRCA1):c.1A>G (p.Met1Val)

https://sugi.bio/variant/brca1-p-met1val

## Summary

**BRCA1 p.Met1Val (c.1A>G)** is classified **Pathogenic/Likely pathogenic** in BRCA1 (ClinVar, Multiple submitters, 25 submitters; last evaluated 2026-06-01). Very rare (popmax 0.00017%, nfe); Associated with Inherited breast cancer and ovarian cancer.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs80357287 · 25 submitters · 7 linked conditions · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the BRCA1 gene that is considered likely disease-causing, submitted by 25 submitters, and is linked to Inherited breast cancer and ovarian cancer.

*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:** [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.Met1Val |
| Coding change (HGVS c.) | c.1A>G |
| MANE Select transcript | [NM_007294](https://www.ncbi.nlm.nih.gov/nuccore/NM_007294) |
| dbSNP | [rs80357287](https://www.ncbi.nlm.nih.gov/snp/rs80357287/) |
| Variant type | single nucleotide variant |
| Location | chr17:43124096-43124096 (GRCh38) |
| ClinVar | [VCV54432](https://www.ncbi.nlm.nih.gov/clinvar/variation/54432/) |

**All HGVS expressions:** `LRG_292:g.93888A>G`, `LRG_292t1:c.1A>G`, `NC_000017.10:g.41276113T>C`, `NC_000017.11:g.43124096T>C`, `NG_005905.2:g.93888A>G`, `NM_001407571.1:c.-188A>G`, `NM_001407581.1:c.1A>G`, `NM_001407582.1:c.1A>G`, `NM_001407583.1:c.1A>G`, `NM_001407585.1:c.1A>G`, `NM_001407587.1:c.1A>G`, `NM_001407590.1:c.1A>G`, `NM_001407591.1:c.1A>G`, `NM_001407593.1:c.1A>G`, `NM_001407594.1:c.1A>G`, `NM_001407596.1:c.1A>G`, `NM_001407597.1:c.1A>G`, `NM_001407598.1:c.1A>G`, `NM_001407602.1:c.1A>G`, `NM_001407603.1:c.1A>G`, `NM_001407605.1:c.1A>G`, `NM_001407610.1:c.1A>G`, `NM_001407611.1:c.1A>G`, `NM_001407612.1:c.1A>G`, `NM_001407613.1:c.1A>G`, `NM_001407614.1:c.1A>G`, `NM_001407615.1:c.1A>G`, `NM_001407616.1:c.1A>G`, `NM_001407617.1:c.1A>G`, `NM_001407618.1:c.1A>G`, `NM_001407619.1:c.1A>G`, `NM_001407620.1:c.1A>G`, `NM_001407621.1:c.1A>G`, `NM_001407622.1:c.1A>G`, `NM_001407623.1:c.1A>G`, `NM_001407624.1:c.1A>G`, `NM_001407625.1:c.1A>G`, `NM_001407626.1:c.1A>G`, `NM_001407627.1:c.1A>G`, `NM_001407628.1:c.1A>G`, `NM_001407629.1:c.1A>G`, `NM_001407630.1:c.1A>G`, `NM_001407631.1:c.1A>G`, `NM_001407632.1:c.1A>G`, `NM_001407633.1:c.1A>G`, `NM_001407634.1:c.1A>G`, `NM_001407635.1:c.1A>G`, `NM_001407636.1:c.1A>G`, `NM_001407637.1:c.1A>G`, `NM_001407638.1:c.1A>G`, `NM_001407639.1:c.1A>G`, `NM_001407640.1:c.1A>G`, `NM_001407641.1:c.1A>G`, `NM_001407642.1:c.1A>G`, `NM_001407644.1:c.1A>G`, `NM_001407645.1:c.1A>G`, `NM_001407646.1:c.1A>G`, `NM_001407647.1:c.1A>G`, `NM_001407648.1:c.1A>G`, `NM_001407649.1:c.1A>G`, `NM_001407652.1:c.1A>G`, `NM_001407653.1:c.1A>G`, `NM_001407654.1:c.1A>G`, `NM_001407655.1:c.1A>G`, `NM_001407656.1:c.1A>G`, `NM_001407657.1:c.1A>G`, `NM_001407658.1:c.1A>G`, `NM_001407659.1:c.1A>G`, `NM_001407660.1:c.1A>G`, `NM_001407661.1:c.1A>G`, `NM_001407662.1:c.1A>G`, `NM_001407663.1:c.1A>G`, `NM_001407664.1:c.1A>G`, `NM_001407665.1:c.1A>G`, `NM_001407666.1:c.1A>G`, `NM_001407667.1:c.1A>G`, `NM_001407668.1:c.1A>G`, `NM_001407669.1:c.1A>G`, `NM_001407670.1:c.1A>G`, `NM_001407671.1:c.1A>G`, `NM_001407672.1:c.1A>G`, `NM_001407673.1:c.1A>G`, `NM_001407674.1:c.1A>G`, `NM_001407675.1:c.1A>G`, `NM_001407676.1:c.1A>G`, `NM_001407677.1:c.1A>G`, `NM_001407678.1:c.1A>G`, `NM_001407679.1:c.1A>G`, `NM_001407680.1:c.1A>G`, `NM_001407681.1:c.1A>G`, `NM_001407682.1:c.1A>G`, `NM_001407683.1:c.1A>G`, `NM_001407684.1:c.1A>G`, `NM_001407685.1:c.1A>G`, `NM_001407686.1:c.1A>G`, `NM_001407687.1:c.1A>G`, `NM_001407688.1:c.1A>G`, `NM_001407689.1:c.1A>G`, `NM_001407690.1:c.1A>G`, `NM_001407691.1:c.1A>G`, `NM_001407694.1:c.-257A>G`, `NM_001407695.1:c.-261A>G`, `NM_001407696.1:c.-402A>G`, `NM_001407697.1:c.-286A>G`, `NM_001407698.1:c.-87A>G`, `NM_001407724.1:c.-257A>G`, `NM_001407725.1:c.-260A>G`, `NM_001407726.1:c.-206A>G`, `NM_001407727.1:c.-257A>G`, `NM_001407730.1:c.-260A>G`, `NM_001407731.1:c.-257A>G`, `NM_001407732.1:c.-87A>G`, `NM_001407733.1:c.-257A>G`, `NM_001407734.1:c.-260A>G`, `NM_001407736.1:c.-87A>G`, `NM_001407738.1:c.-87A>G`, `NM_001407739.1:c.-260A>G`, `NM_001407740.1:c.-260A>G`, `NM_001407741.1:c.-264A>G`, `NM_001407742.1:c.-87A>G`, `NM_001407744.1:c.-87A>G`, `NM_001407748.1:c.-260A>G`, `NM_001407749.1:c.-257A>G`, `NM_001407750.1:c.-87A>G`, `NM_001407751.1:c.-206A>G`, `NM_001407752.1:c.-260A>G`, `NM_001407838.1:c.-260A>G`, `NM_001407841.1:c.-137A>G`, `NM_001407842.1:c.-257A>G`, `NM_001407843.1:c.-257A>G`, `NM_001407845.1:c.-87A>G`, `NM_001407846.1:c.-286A>G`, `NM_001407847.1:c.-260A>G`, `NM_001407849.1:c.-87A>G`, `NM_001407850.1:c.-260A>G`, `NM_001407852.1:c.-87A>G`, `NM_001407853.1:c.-188A>G`, `NM_001407854.1:c.1A>G`, `NM_001407858.1:c.1A>G`, `NM_001407859.1:c.1A>G`, `NM_001407860.1:c.1A>G`, `NM_001407861.1:c.1A>G`, `NM_001407862.1:c.1A>G`, `NM_001407863.1:c.1A>G`, `NM_001407874.1:c.1A>G`, `NM_001407875.1:c.1A>G`, `NM_001407879.1:c.-188A>G`, `NM_001407881.1:c.-134A>G`, `NM_001407882.1:c.-188A>G`, `NM_001407884.1:c.-188A>G`, `NM_001407886.1:c.-188A>G`, `NM_001407887.1:c.-188A>G`, `NM_001407889.1:c.-304A>G`, `NM_001407894.1:c.-188A>G`, `NM_001407895.1:c.-188A>G`, `NM_001407897.1:c.-188A>G`, `NM_001407898.1:c.-134A>G`, `NM_001407899.1:c.-188A>G`, `NM_001407902.1:c.-134A>G`, `NM_001407904.1:c.-188A>G`, `NM_001407906.1:c.-188A>G`, `NM_001407907.1:c.-188A>G`, `NM_001407908.1:c.-188A>G`, `NM_001407909.1:c.-188A>G`, `NM_001407910.1:c.-188A>G`, `NM_001407915.1:c.-188A>G`, `NM_001407916.1:c.-188A>G`, `NM_001407917.1:c.-307A>G`, `NM_001407918.1:c.-188A>G`, `NM_001407919.1:c.1A>G`, `NM_001407920.1:c.-286A>G`, `NM_001407921.1:c.-260A>G`, `NM_001407923.1:c.-260A>G`, `NM_001407924.1:c.-87A>G`, `NM_001407925.1:c.-87A>G`, `NM_001407927.1:c.-260A>G`, `NM_001407928.1:c.-87A>G`, `NM_001407929.1:c.-87A>G`, `NM_001407930.1:c.-257A>G`, `NM_001407932.1:c.-87A>G`, `NM_001407933.1:c.-260A>G`, `NM_001407934.1:c.-264A>G`, `NM_001407936.1:c.-87A>G`, `NM_001407937.1:c.1A>G`, `NM_001407938.1:c.1A>G`, `NM_001407939.1:c.1A>G`, `NM_001407940.1:c.1A>G`, `NM_001407941.1:c.1A>G`, `NM_001407942.1:c.-257A>G`, `NM_001407943.1:c.-260A>G`, `NM_001407944.1:c.-260A>G`, `NM_001407945.1:c.-87A>G`, `NM_001407946.1:c.-188A>G`, `NM_001407947.1:c.-188A>G`, `NM_001407948.1:c.-188A>G`, `NM_001407949.1:c.-188A>G`, `NM_001407950.1:c.-188A>G`, `NM_001407951.1:c.-188A>G`, `NM_001407952.1:c.-188A>G`, `NM_001407953.1:c.-188A>G`, `NM_001407954.1:c.-307A>G`, `NM_001407955.1:c.-188A>G`, `NM_001407956.1:c.-188A>G`, `NM_001407957.1:c.-188A>G`, `NM_001407958.1:c.-188A>G`, `NM_001407965.1:c.-419A>G`, `NM_001407968.1:c.1A>G`, `NM_001407969.1:c.1A>G`, `NM_001407970.1:c.1A>G`, `NM_001407971.1:c.1A>G`, `NM_001407972.1:c.1A>G`, `NM_001407973.1:c.1A>G`, `NM_001407974.1:c.1A>G`, `NM_001407975.1:c.1A>G`, `NM_001407976.1:c.1A>G`, `NM_001407977.1:c.1A>G`, `NM_001407978.1:c.1A>G`, `NM_001407979.1:c.1A>G`, `NM_001407980.1:c.1A>G`, `NM_001407981.1:c.1A>G`, `NM_001407982.1:c.1A>G`, `NM_001407983.1:c.1A>G`, `NM_001407984.1:c.1A>G`, `NM_001407985.1:c.1A>G`, `NM_001407986.1:c.1A>G`, `NM_001407990.1:c.1A>G`, `NM_001407991.1:c.1A>G`, `NM_001407992.1:c.1A>G`, `NM_001407993.1:c.1A>G`, `NM_001408392.1:c.1A>G`, `NM_001408396.1:c.1A>G`, `NM_001408397.1:c.1A>G`, `NM_001408398.1:c.1A>G`, `NM_001408399.1:c.1A>G`, `NM_001408400.1:c.1A>G`, `NM_001408401.1:c.1A>G`, `NM_001408402.1:c.1A>G`, `NM_001408403.1:c.1A>G`, `NM_001408404.1:c.1A>G`, `NM_001408406.1:c.1A>G`, `NM_001408407.1:c.1A>G`, `NM_001408408.1:c.1A>G`, `NM_001408409.1:c.1A>G`, `NM_001408410.1:c.-260A>G`, `NM_001408411.1:c.1A>G`, `NM_001408412.1:c.1A>G`, `NM_001408413.1:c.1A>G`, `NM_001408414.1:c.1A>G`, `NM_001408415.1:c.1A>G`, `NM_001408416.1:c.1A>G`, `NM_001408418.1:c.1A>G`, `NM_001408419.1:c.1A>G`, `NM_001408420.1:c.1A>G`, `NM_001408421.1:c.1A>G`, `NM_001408422.1:c.1A>G`, `NM_001408423.1:c.1A>G`, `NM_001408424.1:c.1A>G`, `NM_001408425.1:c.1A>G`, `NM_001408426.1:c.1A>G`, `NM_001408427.1:c.1A>G`, `NM_001408428.1:c.1A>G`, `NM_001408429.1:c.1A>G`, `NM_001408430.1:c.1A>G`, `NM_001408431.1:c.1A>G`, `NM_001408432.1:c.1A>G`, `NM_001408433.1:c.1A>G`, `NM_001408434.1:c.1A>G`, `NM_001408435.1:c.1A>G`, `NM_001408436.1:c.1A>G`, `NM_001408437.1:c.1A>G`, `NM_001408438.1:c.1A>G`, `NM_001408439.1:c.1A>G`, `NM_001408440.1:c.1A>G`, `NM_001408441.1:c.1A>G`, `NM_001408442.1:c.1A>G`, `NM_001408443.1:c.1A>G`, `NM_001408444.1:c.1A>G`, `NM_001408445.1:c.1A>G`, `NM_001408446.1:c.1A>G`, `NM_001408447.1:c.1A>G`, `NM_001408448.1:c.1A>G`, `NM_001408450.1:c.1A>G`, `NM_001408451.1:c.1A>G`, `NM_001408452.1:c.-260A>G`, `NM_001408454.1:c.-87A>G`, `NM_001408455.1:c.-257A>G`, `NM_001408456.1:c.-257A>G`, `NM_001408459.1:c.-87A>G`, `NM_001408460.1:c.-87A>G`, `NM_001408461.1:c.-87A>G`, `NM_001408462.1:c.-260A>G`, `NM_001408463.1:c.-260A>G`, `NM_001408464.1:c.-87A>G`, `NM_001408465.1:c.-261A>G`, `NM_001408466.1:c.-260A>G`, `NM_001408467.1:c.-87A>G`, `NM_001408468.1:c.-257A>G`, `NM_001408472.1:c.1A>G`, `NM_001408473.1:c.1A>G`, `NM_001408474.1:c.1A>G`, `NM_001408475.1:c.1A>G`, `NM_001408476.1:c.1A>G`, `NM_001408478.1:c.-188A>G`, `NM_001408479.1:c.-188A>G`, `NM_001408480.1:c.-188A>G`, `NM_001408481.1:c.-188A>G`, `NM_001408482.1:c.-333A>G`, `NM_001408483.1:c.-188A>G`, `NM_001408484.1:c.-188A>G`, `NM_001408485.1:c.-188A>G`, `NM_001408489.1:c.-188A>G`, `NM_001408490.1:c.-188A>G`, `NM_001408491.1:c.-188A>G`, `NM_001408492.1:c.-304A>G`, `NM_001408493.1:c.-188A>G`, `NM_001408494.1:c.1A>G`, `NM_001408495.1:c.1A>G`, `NM_001408496.1:c.-87A>G`, `NM_001408497.1:c.-264A>G`, `NM_001408498.1:c.-87A>G`, `NM_001408499.1:c.-260A>G`, `NM_001408500.1:c.-260A>G`, `NM_001408501.1:c.-257A>G`, `NM_001408502.1:c.-188A>G`, `NM_001408503.1:c.-260A>G`, `NM_001408504.1:c.-260A>G`, `NM_001408506.1:c.-188A>G`, `NM_001408507.1:c.-188A>G`, `NM_001408508.1:c.-188A>G`, `NM_001408509.1:c.-188A>G`, `NM_001408513.1:c.-307A>G`, `NM_001408514.1:c.-188A>G`, `NM_007294.4:c.1A>G`, `NM_007297.4:c.-87A>G`, `NM_007298.4:c.1A>G`, `NM_007299.4:c.1A>G`, `NM_007300.4:c.1A>G`, `NM_007304.2:c.1A>G`, `NR_027676.2:n.203A>G`, `U14680.1:n.120A>G`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.794, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **start-loss** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 23.6**. 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.*
- 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 **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,177,632 in the highest group · 3/1,459,096 alleles overall — very rare (popmax 0.00017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,410 |
| European (non-Finnish) (grpmax) | 0.00017% | 588,817 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **1** lies in a modified residue (n-acetylmethionine).

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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (23 Pathogenic, 1 Likely Pathogenic).

**Submission history:** 25 submissions (2004–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Sharing Clinical Reports Project (SCRP) | Pathogenic | no assertion criteria provided | clinical testing | 2010-02-01 |
| Molecular Genetics Laboratory, University of Michigan | Pathogenic | criteria provided, single submitter | clinical testing | 2014-11-03 |
| Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Pathogenic | no assertion criteria provided | research | 2014-01-31 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Pathogenic | no assertion criteria provided | clinical testing |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2021-01-05 |
| Center for Precision Medicine, Meizhou People's Hospital | Pathogenic | no assertion criteria provided | literature only |  |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2018-07-02 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-11 |
| BRCAlab, Lund University | Pathogenic | no assertion criteria provided | clinical testing | 2020-03-02 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2014-09-04 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-14 |
| Brotman Baty Institute, University of Washington |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-09 |
| Breast Cancer Information Core (BIC) (BRCA1) | Pathogenic | no assertion criteria provided | clinical testing | 2004-02-20 |
| 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 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2019-10-28 |
| 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 | 2023-10-02 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2019-10-14 |
| NHS Central & South Genomic Laboratory Hub | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Molecular Pathology, Peter Maccallum Cancer Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-07 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-17 |
| Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Pathogenic | criteria provided, single submitter | clinical testing | 2026-06-01 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-01 |

## Associated conditions {#conditions}

[Inherited breast cancer and ovarian cancer](https://sugi.bio/atlas/disease/inherited-breast-cancer-and-ovarian-cancer/), [hereditary breast ovarian cancer syndrome](https://sugi.bio/atlas/disease/hereditary-breast-ovarian-cancer-syndrome/), [breast cancer](https://sugi.bio/atlas/disease/breast-cancer/), [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/), [breast neoplasm](https://sugi.bio/atlas/disease/breast-neoplasm/).

**Reported phenotype names (ClinVar):** Inherited breast cancer and ovarian cancer, Breast-ovarian cancer, familial, susceptibility to, 1, Hereditary cancer-predisposing syndrome, not provided, Breast neoplasm, Hereditary breast ovarian cancer syndrome, Malignant tumor of breast, Familial cancer of breast, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary.

## Same-residue context {#hotspot}

Residue **1** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [BRCA1 p.Met1Ile](/variant/brca1-p-met1ile), [BRCA1 p.Met1Thr](/variant/brca1-p-met1thr), [BRCA1 p.Met1Arg](/variant/brca1-p-met1arg), [BRCA1 p.Met1Lys](/variant/brca1-p-met1lys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRCA1 variant pages (same residue, condition, or type): [BRCA1 p.Met1Arg](/variant/brca1-p-met1arg), [BRCA1 p.Met1Thr](/variant/brca1-p-met1thr), [BRCA1 p.Met1Ile](/variant/brca1-p-met1ile), [BRCA1 p.Met1Lys](/variant/brca1-p-met1lys), [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 54432). 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.*