NM_007294.4:c.738del

BRCA1 · NP_009225.1:p.(Asn247ThrfsTer51) · NM_007294.4

GRCh37: chr17:41246809 TC>T · GRCh38: chr17:43094792 TC>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

Pathogenic

PVS1 very strong PM5 strong

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Asn247ThrfsTer51)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_007294.4:c.738del (p.Asn247ThrfsTer51) is a frameshift deletion in BRCA1 exon 10 predicted to produce a premature termination codon and trigger nonsense-mediated decay.

PVS1 (Very Strong) is assigned per ENIGMA Specifications Table 4: PTC variants in BRCA1 exon 10 receive full PVS1 weight.

PM5_Strong (PTC) is assigned per ENIGMA Specifications Table 4: BRCA1 exon 10 PTC variants receive PM5_Strong under the PTC-specific PM5 framework.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases. PM2 is not applicable per ENIGMA rules — deletions are excluded from PM2 application.

ENIGMA criteria PS2/PM6, PS3/BS3 (Table 9), PM1, PM4, PP2, PP3, BP1, BP3, BP4, BP7, BP2, PP5, and BP6 are not applicable to this frameshift variant under the ENIGMA v1.2 specification framework.

No publications with variant-specific evidence for NM_007294.4:c.738del were identified in the literature review. Seven full-text papers and associated abstracts were reviewed; none mention this exact variant.

Final determination: ENIGMA BRCA1/BRCA2 v1.2 Table 3: 1 Very Strong criterion plus at least 1 Strong criterion combines to Pathogenic.

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	NM_007294.4:c.738del is a frameshift deletion in BRCA1 exon 10 that creates a premature termination codon at p.(Asn247ThrfsTer51). Loss of function is an established disease mechanism for BRCA1. Under ENIGMA Specifications Table 4, PTC variants in exon 10 are assigned PVS1 at full strength. The truncation occurs early in the coding sequence (codon 247 of 1864), far upstream of the clinically important BRCT domains (aa 1650-1857), and is expected to trigger nonsense-mediated decay.	vcep_specifications_table4_v1_2_2024_11_18 cspec
PS1	N/A	PS1 applies to missense substitutions or splicing variants with the same predicted impact as a previously classified pathogenic variant. This is a frameshift deletion, not a missense or splicing variant.
PS2	N/A	ENIGMA v1.2 specifies PM6 (and PS2) are not applicable for BRCA1/2: BRCA1/2-related cancers are relatively common and there is no information to calibrate the predictive capacity of de novo occurrences.
PS3	N/A	ENIGMA Table 9 functional assay assignments apply to missense and synonymous variants only. This is a frameshift variant; functional assessment is captured through PVS1 per the ENIGMA framework.
PS4	Not assessed	No case-control data meeting ENIGMA PS4 criteria (p≤0.05, OR≥4, CI excludes 2.0) was identified for this variant. The variant is absent from gnomAD population datasets, precluding a case-control comparison from available data.
PS5	N/A	PP5 is not for use per the ClinGen Sequence Variant Interpretation VCEP Review Committee; excluded from the ENIGMA BRCA1/2 specification.
PM1	N/A	PM1 is not applicable per ENIGMA v1.2; mutational hotspot and functional domain evidence is considered as a component of bioinformatic analysis (PP3/BP4).
PM2	N/A	ENIGMA v1.2 specifies: 'Do not apply for insertion, deletion or delins variants.' This variant is a single-nucleotide deletion; PM2 is excluded by VCEP rule regardless of gnomAD absence.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	N/A	Skipped per adjudication instructions.
PM4	N/A	PM4 is not applicable per ENIGMA v1.2; protein length changes due to in-frame deletions/insertions are captured under the PP3/BP4 bioinformatic framework. This variant is a frameshift, not an in-frame change.
PM5	Met	Under ENIGMA Specifications Table 4, PTC variants in BRCA1 exon 10 are assigned PM5_Strong (PTC). This criterion provides additional weight for protein termination codon variants in exons where proven pathogenic PTC variants have been previously observed. BRCA1 exon 10 is the largest coding exon and contains numerous established pathogenic PTC variants.	vcep_specifications_table4_v1_2_2024_11_18 cspec
PM6	N/A	ENIGMA v1.2 specifies PM6 is not applicable for BRCA1/2: BRCA1/2-related cancers are relatively common and there is no information to calibrate the predictive capacity of de novo occurrences.
PP1	Not assessed	No co-segregation data meeting ENIGMA PP1 criteria (quantitative Bayes score LR≥2.08) is available for this variant.
PP2	N/A	PP2 is not applicable per ENIGMA v1.2. This criterion is excluded from the BRCA1/2 specification.
PP3	N/A	ENIGMA PP3 applies to (a) missense/in-frame variants inside a clinically important functional domain with BayesDel≥0.28, or (b) variants with predicted splicing impact (SpliceAI≥0.2). This is a frameshift variant; SpliceAI max delta score is 0.15 (<0.2 threshold). PP3 is not applicable to frameshift null variants per the ENIGMA bioinformatic code flowchart (Figure 1A).	spliceai cspec
PP4	Not assessed	No clinical-history likelihood ratio data is available for this variant in the Li et al. 2020 (PMID:31853058) BRCA1 clinical_history_LR table. The variant c.738del was not found in the table, precluding PP4/BP5 assessment via this calibrated dataset.	PMID:31853058
PP5	N/A	PP5 is not for use per ENIGMA v1.2; excluded by ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.
BA1	Not met	BA1 requires filter allele frequency >0.1% in gnomAD non-founder populations. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 threshold is not satisfied.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires FAF>0.01% (Strong) or FAF>0.002% (Supporting) in gnomAD non-founder populations. The variant is absent from all gnomAD datasets. Neither BS1 threshold is satisfied.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	BS2 requires evidence of co-occurrence with a pathogenic variant in the absence of Fanconi anemia features. No proband-level co-occurrence data is available for this variant.
BS3	N/A	ENIGMA BS3 functional assay assessments (Table 9) apply to missense and synonymous variants only. This is a frameshift null variant; functional evidence is captured through the PVS1 framework.
BS4	Not assessed	No lack-of-segregation data meeting ENIGMA BS4 criteria (quantitative Bayes score LR≤0.48) is available for this variant.
BP1	N/A	ENIGMA BP1_Strong applies to silent substitutions, missense, or in-frame insertion/deletion/delins variants outside clinically important functional domains with SpliceAI≤0.1. This is an out-of-frame (frameshift) deletion and does not qualify under the BP1 rule.
BP2	N/A	BP2 is not applicable per ENIGMA v1.2; BP2 is applied only in the context of BS2 and is not independently assigned.
BP3	N/A	BP3 is not applicable per ENIGMA v1.2; in-frame deletions/insertions in repetitive regions are captured by the broader bioinformatic prediction and domain analysis framework.
BP4	N/A	ENIGMA BP4 applies to missense or in-frame variants inside clinically important functional domains with BayesDel≤0.15 AND SpliceAI≤0.1, or to silent/intronic variants with SpliceAI≤0.1. This is a frameshift null variant and does not meet the variant-type requirements for BP4.
BP5	Not assessed	No clinical-history likelihood ratio data is available for this variant in the Li et al. 2020 (PMID:31853058) BRCA1 clinical_history_LR table. Variant not found in the calibrated dataset.	PMID:31853058
BP6	N/A	BP6 is not for use per ENIGMA v1.2; excluded by ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.
BP7	N/A	ENIGMA BP7 applies to silent and intronic variants, as well as missense/in-frame variants for RNA-level splicing assays. This is a frameshift null variant and does not fall within BP7 scope under the ENIGMA specification (Figure 1B).

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