Variant classification summary

NM_000057.4:c.2207_2212delinsTAGATTC

BLM · NP_000048.1:p.(Tyr736LeufsTer5) · NM_000057.4

GRCh37: chr15:91310153 ATCTGA>TAGATTC · GRCh38: chr15:90766923 ATCTGA>TAGATTC

Gene: BLM Transcript: NM_000057.4

Final call

Pathogenic

PVS1 very strong PS3 strong PM2 supporting PM3 supporting BP5 supporting benign

Variant details

Gene

BLM

Transcript

NM_000057.4

Protein

NP_000048.1:p.(Tyr736LeufsTer5)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong reflects the truncating frameshift and demonstrated loss of BLM transcript and protein.

2

Pathogenic: PS3 strong reflects damaging cellular effects and rescue by wild-type BLM.

3

Pathogenic: PM2 supporting reflects absence from gnomAD v2.1 and v4.1.

4

Pathogenic: PM3 supporting reflects homozygosity of the exact variant in Bloom syndrome models.

5

BP5 supporting benign is insufficient alone to satisfy a benign combination rule.

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong pathogenic criterion plus one strong pathogenic criterion satisfies Pathogenic; the single supporting benign BP5 criterion does not satisfy a benign rule, so evidence is not conflicting.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Met at very strong: the exon 10 frameshift creates p.Tyr736LeufsTer5 and variant-specific studies show approximately 80% lower BLM mRNA with absent full-length protein.	pvs1_variant_assessment PMID:10521302 PMID:26788541 PMID:25741868
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: parental testing and documented absence of family history are unavailable, so confirmed de novo occurrence cannot be established.
PS3	Met	Met at strong: homozygous blmAsh cells had approximately 80% less BLM mRNA, absent detectable protein, abnormal sister-chromatid exchange, and restoration toward normal after wild-type rescue.	PMID:10521302 PMID:26788541
PS4	Not met	Not met: exact-variant case-control enrichment was not shown; the aggregate BLM study had OR 8.67 but 95% CI 0.69-455.36 included 1.	PMID:26358404 PMID:26788541 PMID:29506128
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, consistent with the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Met	Met at supporting: the exact BLM variant was homozygous in Bloom-syndrome individuals, establishing two pathogenic copies in trans for this recessive disorder.	PMID:10521302 PMID:26788541
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental testing or documented de novo observation is available to support an assumed de novo event.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are documented, preventing evaluation of co-segregation.
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the variant is a frameshift, outside PP3's missense or splice-region/intronic scope despite SpliceAI max delta 0.027.
PP4	Not met	Not met: pancreatic neoplasia with family history and a concurrent BRCA1 variant is not highly specific for a single genetic etiology.	PMID:29506128
PP5	Not met	Not met: ClinVar has only multiple laboratory submissions and no expert-panel classification for this exact variant.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no filtering allele frequency reaches the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the generic BS1 filtering-frequency threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no age-qualified healthy adult individual-level observation is documented for evaluating the BS2 genotype requirement.
BS3	Not met	Not met: variant-specific cells showed reduced BLM expression and abnormal cellular phenotypes, with correction toward normal after wild-type complementation rather than preserved function.	PMID:10521302 PMID:26788541
BS4	Not assessed	Not assessed: no affected relatives with documented absence of the variant are reported to demonstrate lack of segregation.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase-resolved cis-linked pathogenic variant was reported, and BP2's dominant trans branch does not apply to recessive BLM-related Bloom syndrome.	PMID:10521302 PMID:26788541 PMID:29506128
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the variant is a frameshift, so SpliceAI max delta 0.027 cannot support BP4 by showing no gene-product impact.
BP5	Met	Met: the exact BLM variant co-occurred with BRCA1 c.68_69delAG in the same pancreatic-neoplasm patient.	PMID:29506128
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a frameshift variant.	generic_acmg_combination_rules

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