# NM_000057.4(BLM):c.1288T>C (p.Tyr430His)

https://sugi.bio/variant/blm-p-tyr430his

## Summary

**BLM p.Tyr430His (c.1288T>C)** is classified **Conflicting classifications of pathogenicity** in BLM (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.0766); Very rare (popmax 0.000593%, nfe); Associated with Bloom syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1314473930 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.000593%, nfe)

## For patients & families {#patients}

This is a change in the BLM gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 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.Tyr430His |
| Coding change (HGVS c.) | c.1288T>C |
| MANE Select transcript | [NM_000057](https://www.ncbi.nlm.nih.gov/nuccore/NM_000057) |
| dbSNP | [rs1314473930](https://www.ncbi.nlm.nih.gov/snp/rs1314473930/) |
| Variant type | single nucleotide variant |
| Location | chr15:90760661-90760661 (GRCh38) |
| ClinVar | [VCV649548](https://www.ncbi.nlm.nih.gov/clinvar/variation/649548/) |

**All HGVS expressions:** `LRG_20:g.48290T>C`, `NC_000015.10:g.90760661T>C`, `NC_000015.9:g.91303891T>C`, `NG_007272.1:g.48290T>C`, `NM_000057.2:c.1288T>C`, `NM_000057.4:c.1288T>C`, `NM_001287246.2:c.1288T>C`, `NM_001287247.2:c.1288T>C`, `NM_001287248.2:c.163T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0766)
- REVEL 0.017 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.09 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.99, GERP -5.33 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.06**. 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 0.96** across the covering region of the MANE Select transcript (90,747,393–90,763,063), spanning 15,670 bp. Chi-square p 0.23. 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 **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,179,850 in the highest group · 7/1,613,860 alleles overall — very rare (popmax 0.000593%, nfe).

*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 **430** lies in the 'necessary for interaction with spidr' region.

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.Tyr430His falls in the necessary for interaction with spidr 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-21.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely benign).

**Submission history:** 3 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-11-16 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-21 |

## 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, Hereditary cancer-predisposing syndrome, Bloom-Torre-Machacek syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome.

## Same-residue context {#hotspot}

Residue **430** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [BLM p.Tyr430Ter](/variant/blm-p-tyr430ter), [BLM p.Tyr430_Arg431delinsTer](/variant/blm-p-tyr430-arg431delinster). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BLM variant pages (same residue, condition, or type): [BLM p.Tyr430Phe](/variant/blm-p-tyr430phe), [BLM p.Tyr430=](/variant/blm-p-tyr430), [BLM p.Tyr430_Arg431delinsTer](/variant/blm-p-tyr430-arg431delinster), [BLM p.Tyr430Ter](/variant/blm-p-tyr430ter), [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).

### 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 649548). 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.*