# NM_000057.4(BLM):c.2695C>T (p.Arg899Ter)

https://sugi.bio/variant/blm-p-arg899ter

## Summary

**BLM p.Arg899Ter (c.2695C>T)** is classified **Pathogenic** in BLM (ClinVar, Multiple submitters, 25 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0211%, nfe); Associated with Bloom syndrome.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs587779884 · 25 submitters · 2 linked conditions · ultra-rare (popmax 0.0211%, nfe)

## For patients & families {#patients}

This is a change in the BLM gene that is considered disease-causing, submitted by 25 submitters, and is linked to Bloom 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Neonatal |
| Prevalence | 1-9 / 100 000 (Specific population) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BLM is a diagnostic-grade gene on 19 Genomics England panels |

**Commonly reported features of Bloom syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Growth delay — Very frequent (99-80%)
- Intrauterine growth retardation — Very frequent (99-80%)
- Small for gestational age — Very frequent (99-80%)
- Abnormality of the immune system — Very frequent (99-80%)
- Decreased circulating antibody level — Very frequent (99-80%)
- Severe postnatal growth retardation — Very frequent (99-80%)
- Adipose tissue loss — Very frequent (99-80%)
- Malar flattening — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000915/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.Arg899Ter |
| Coding change (HGVS c.) | c.2695C>T |
| MANE Select transcript | [NM_000057](https://www.ncbi.nlm.nih.gov/nuccore/NM_000057) |
| dbSNP | [rs587779884](https://www.ncbi.nlm.nih.gov/snp/rs587779884/) |
| Variant type | single nucleotide variant |
| Location | chr15:90784953-90784953 (GRCh38) |
| ClinVar | [VCV127491](https://www.ncbi.nlm.nih.gov/clinvar/variation/127491/) |

**All HGVS expressions:** `LRG_20:g.72582C>T`, `LRG_20t1:c.2695C>T`, `NC_000015.10:g.90784953C>T`, `NC_000015.9:g.91328183C>T`, `NG_007272.1:g.72582C>T`, `NM_000057.4:c.2695C>T`, `NM_001287246.2:c.2695C>T`, `NM_001287247.2:c.2695C>T`, `NM_001287248.2:c.1570C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.34) — consistent with the pathogenic call
- Conservation: phyloP 0.447, GERP -3.99, phastCons 0.99 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.847, pLI 8.7183e-22. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 14 of 22**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 37.0**. 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 deltas (raw): acceptor loss **0.34**, donor loss **0.00**, acceptor gain **0.16**, donor gain **0.01**. Largest is acceptor loss, 32 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.16**, donor gain **0.01**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.34** (gain), gain 0.34 / loss 0.29. SpliceAI calls loss. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0211%** (nfe) · FAF95 0.0189% · FAF99 0.0181% · 249/1,179,986 in the highest group · 255/1,613,904 alleles overall — ultra-rare (popmax 0.0211%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0211% | 4,739 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,497 |
| African / African-American | 0.00134% | 74,890 |

*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 gene assoc. with recessive phenotype, 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):

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

## Protein context {#protein}

Residue **899** lies in the '3' overhang dna-binding' region; an α-helix; the helicase c-terminal domain.

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. p.Arg899Ter falls in the 3 overhang dna-binding region. 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-27.

**Submitter consensus:** conflicting (23 Pathogenic, 1 Likely pathogenic, 1 not provided).

**Submission history:** 25 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Pathogenic | criteria provided, single submitter | clinical testing | 2017-04-28 |
| Genetic Services Laboratory, University of Chicago | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-18 |
| Sema4, Sema4 | Pathogenic | criteria provided, single submitter | curation | 2022-01-06 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-23 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-26 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2017-09-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-27 |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-10 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-15 |
| 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 | 2018-04-23 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | 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 |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| Neuberg Centre For Genomic Medicine, NCGM | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-06 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-18 |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-18 |
| Counsyl | Likely pathogenic | no assertion criteria provided | literature only | 2014-06-20 |
| GeneKor MSA | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-15 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2019-03-28 |
| GenomeConnect - Invitae Patient Insights Network | not provided | no classification provided | phenotyping only |  |
| Otogenetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-19 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-17 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Bloom syndrome, not provided, Hereditary cancer-predisposing syndrome, BLM-related disorder, none provided, Bloom-Torre-Machacek syndrome, BLM-related condition, Tumor predisposition, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary.

## Similar variants {#similar}

Related BLM variant pages (same residue, condition, or type): [BLM p.Arg899Gln](/variant/blm-p-arg899gln), [BLM p.Arg899Gly](/variant/blm-p-arg899gly), [BLM p.Arg899=](/variant/blm-p-arg899), [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 2026-10-14); 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 2026-10-14); 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 127491). 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.*