# NM_000057.4(BLM):c.511dup (p.Thr171fs)

https://sugi.bio/variant/blm-p-thr171fs

## Summary

**BLM p.Thr171fs (c.511dup)** is classified **Pathogenic/Likely pathogenic** in BLM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-11). Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2505392993 · 3 submitters · 2 linked conditions · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the BLM gene that is considered likely disease-causing, submitted by 3 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.Thr171fs |
| Coding change (HGVS c.) | c.511dup |
| MANE Select transcript | [NM_000057](https://www.ncbi.nlm.nih.gov/nuccore/NM_000057) |
| dbSNP | [rs2505392993](https://www.ncbi.nlm.nih.gov/snp/rs2505392993/) |
| Variant type | Duplication |
| Location | chr15:90749778-90749779 (GRCh38) |
| ClinVar | [VCV1745463](https://www.ncbi.nlm.nih.gov/clinvar/variation/1745463/) |

**All HGVS expressions:** `LRG_20:g.37408dup`, `LRG_20t1:c.511dup`, `NC_000015.10:g.90749779dup`, `NC_000015.9:g.91293009dup`, `NG_007272.1:g.37408dup`, `NM_000057.2:c.511dupA`, `NM_000057.3:c.511dupA`, `NM_000057.4:c.511dup`, `NM_001287246.2:c.511dup`, `NM_001287247.2:c.511dup`, `NM_001287248.2:c.-781dup`

## 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 -1.741, GERP -5.33 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — 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 3 of 22**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.000183% · FAF99 0.00012% · 1/90,978 in the highest group · 7/1,460,284 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 90,978 |
| European (non-Finnish) | 0.000509% | 196,513 |

*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 **171** lies in a modified residue (phosphothreonine).

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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-11.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2022–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-07-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-18 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-01-11 |

## 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, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary neoplastic syndrome, Bloom-Torre-Machacek syndrome.

## Similar variants {#similar}

Related BLM variant pages (same residue, condition, or type): [BLM p.Thr171Ala](/variant/blm-p-thr171ala), [BLM p.Thr171Ile](/variant/blm-p-thr171ile), [BLM p.Thr171Lys](/variant/blm-p-thr171lys), [BLM p.Thr171=](/variant/blm-p-thr171), [BLM p.Ala481fs](/variant/blm-p-ala481fs), [BLM p.Asp467fs](/variant/blm-p-asp467fs), [BLM p.Leu107fs](/variant/blm-p-leu107fs), [BLM p.Leu342fs](/variant/blm-p-leu342fs).

### 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 1745463). 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.*