# NM_000057.4(BLM):c.3108C>T (p.Cys1036=)

https://sugi.bio/variant/blm-p-cys1036

## Summary

**BLM p.Cys1036= (c.3108C>T)** is classified **Likely benign** in BLM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-16). No allele count reported in gnomAD v4.1 (AN 1,605,614); Associated with hereditary neoplastic syndrome.

**At a glance:** Likely benign · review: Multiple submitters · 2 submitters · 2 linked conditions · no allele count reported in gnomAD v4.1 (AN 1,605,614)

## For patients & families {#patients}

This is a change in the BLM gene that is classified as likely benign — not considered disease-causing, 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 | [BLM](https://sugi.bio/atlas/gene/BLM/) |
| Protein change (HGVS p.) | p.Cys1036= |
| Coding change (HGVS c.) | c.3108C>T |
| MANE Select transcript | [NM_000057](https://www.ncbi.nlm.nih.gov/nuccore/NM_000057) |
| Variant type | single nucleotide variant |
| Location | chr15:90794255-90794255 (GRCh38) |
| ClinVar | [VCV3261041](https://www.ncbi.nlm.nih.gov/clinvar/variation/3261041/) |

**All HGVS expressions:** `LRG_20:g.81884C>T`, `LRG_20t1:c.3108C>T`, `NC_000015.10:g.90794255C>T`, `NC_000015.9:g.91337485C>T`, `NG_007272.1:g.81884C>T`, `NM_000057.4:c.3108C>T`, `NM_001287246.2:c.3108C>T`, `NM_001287247.2:c.3108C>T`, `NM_001287248.2:c.1983C>T`

## Computational & population evidence {#evidence}

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

- **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 1.356, GERP -2.01, phastCons 1 — weakly conserved position
- CADD: **PHRED 8.458**. 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: **no allele count reported in gnomAD v4.1 (AN 1,605,614)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**BLM** population constraint: LOEUF 0.847, pLI 8.7183e-22, missense-Z 1.9677; ClinGen dosage — haploinsufficiency 30, 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):

- **colorectal cancer** — Limited (AD)
- **Bloom syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **1036** lies in a UniProt-annotated variant site (in blm); a binding site.

AlphaFold model confidence (whole protein): pLDDT 61.10, 30% of residues very-high.

**16 experimental structure(s)** (PDB): [2KV2](https://www.rcsb.org/structure/2KV2), [2MH9](https://www.rcsb.org/structure/2MH9), [2RRD](https://www.rcsb.org/structure/2RRD), [3WE2](https://www.rcsb.org/structure/3WE2), [3WE3](https://www.rcsb.org/structure/3WE3), [4CDG](https://www.rcsb.org/structure/4CDG).

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

*Describes the biological roles of BLM (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:** BLM's established molecular role includes four-way junction DNA binding. In Reactome, BLM is annotated in disease pathway(s) including **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function**, **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function**.

**Disease mechanism (Reactome):** BLM loss or alteration is curated in [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331), [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), [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192).

### Pathways affected {#pathways}

BLM participates in **17 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [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 |
| [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 |
| [Processive synthesis on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174414) | 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 |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | electronic |

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

**Molecular function:** four-way junction DNA binding, Y-form DNA binding, bubble DNA binding, p53 binding, DNA binding, DNA helicase activity.

**Biological process:** regulation of cyclin-dependent protein serine/threonine kinase activity, telomere maintenance, double-strand break repair via homologous recombination, DNA double-strand break processing, DNA damage response, mitotic G2 DNA damage checkpoint signaling.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-16.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-16 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [Bloom syndrome](https://sugi.bio/atlas/disease/bloom-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Bloom syndrome, Hereditary Cancer Syndrome, Tumor predisposition, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Bloom-Torre-Machacek syndrome.

## Same-residue context {#hotspot}

Residue **1036** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BLM p.Cys1036Phe](/variant/blm-p-cys1036phe). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BLM variant pages (same residue, condition, or type): [BLM p.Cys1036Ser](/variant/blm-p-cys1036ser), [BLM p.Cys1036Tyr](/variant/blm-p-cys1036tyr), [BLM p.Cys1036Phe](/variant/blm-p-cys1036phe), [BLM c.1087+1G>A](/variant/blm-c-1087-plus-1g-a), [BLM c.1088-1G>A](/variant/blm-c-1088-minus-1g-a), [BLM c.1220+2T>C](/variant/blm-c-1220-plus-2t-c), [BLM c.1220+2T>G](/variant/blm-c-1220-plus-2t-g), [BLM c.1882+2T>C](/variant/blm-c-1882-plus-2t-c).

### 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 3261041). 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.*