NM_007294.3:c.5407-10G>A

BRCA1 · NP_009225.1:p.? · NM_007294.3

GRCh37: chr17:41199730 C>T · GRCh38: chr17:43047713 C>T

Gene: BRCA1 Transcript: NM_007294.3

Final call

PP3 supporting PP5 supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA1 c.5407-10G>A (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the current aggregate classification is Likely Pathogenic with expert-panel review.

This variant is absent from gnomAD v4.1 and is present only once in gnomAD v2.1 (1/251448 alleles; AF 3.98e-06), which is too low for benign population criteria but does not satisfy the BRCA1 ENIGMA requirement for complete absence from gnomAD for PM2.

In published BRCA1 functional and RNA studies, this variant showed retention of 8 nucleotides from intron 22 and partial functional impact rather than a clearly damaging or clearly benign result, so the ENIGMA BRCA1 functional tables indicate that PS3 and BS3 are not met.

SpliceAI predicts a strong splice effect for this variant with a maximum delta score of 1.00, which exceeds the BRCA1 ENIGMA PP3 threshold of 0.20 for intronic variants outside the native +/-1,2 splice sites and supports PP3 at Supporting strength.

Final determination: Under the ENIGMA BRCA1/BRCA2 Specification Table 3 criteria-combination framework, two supporting pathogenic criteria without additional qualifying pathogenic or benign criteria correspond to an Uncertain Significance classification.

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	Not met	This intronic variant is outside the canonical +/-1,2 splice positions, so it does not qualify for default PVS1 application. Available BRCA1 functional/splicing data show retention of 8 nucleotides from intron 22 with partial functional impact rather than a clear loss-of-function result, so current evidence does not support PVS1 or PVS1(RNA).	cspec pvs1_variant_assessment vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:30209399 PMID:31143303
PS1	Not assessed	No evidence was identified showing that this variant has the same established splicing consequence as a previously classified pathogenic or likely pathogenic BRCA1 variant, so PS1 was not assessed.	cspec
PS2	N/A	PS2 is not used in this BRCA1 ENIGMA specification.	cspec
PS3	Not met	Published functional and RNA studies for this exact variant showed partial impact rather than a clearly damaging effect. The BRCA1 ENIGMA functional table therefore indicates that PS3 is not met for this variant.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:30209399 PMID:31143303
PS4	Not assessed	No case-control dataset or other prevalence analysis was identified showing that this variant is significantly enriched in affected individuals compared with controls, so PS4 was not assessed.	cspec clinvar
PM1	N/A	PM1 is not applicable in the BRCA1 ENIGMA specification for this variant type.	cspec
PM2	Not met	This variant is not absent from population databases. It is seen once in gnomAD v2.1 (1/251448 alleles; AF 3.98e-06) even though it is absent from gnomAD v4.1, so the BRCA1 ENIGMA requirement for absence from gnomAD is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified for this variant occurring with a second BRCA1 variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	PM4 is not used in this BRCA1 ENIGMA specification.	cspec
PM5	N/A	PM5 in this BRCA1 ENIGMA framework is used for qualifying protein-termination-codon contexts or missense substitutions, and that situation was not identified for this intronic variant.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is not used in this BRCA1 ENIGMA specification.	cspec
PP1	Not assessed	No informative segregation dataset was identified for this variant, so PP1 was not assessed.	cspec
PP2	N/A	PP2 is not used in this BRCA1 ENIGMA specification.	cspec
PP3	Met	Splice prediction supports an abnormal splicing effect. SpliceAI shows a maximum delta score of 1.00, which is above the BRCA1 ENIGMA PP3 threshold of 0.20 for intronic variants outside the native +/-1,2 splice sites, so PP3 is met at Supporting strength.	cspec spliceai
PP4	Not assessed	No usable BRCA1 clinical-history likelihood ratio was identified for this variant, so PP4 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.	cspec clinvar
BA1	Not met	Population frequency does not meet the BRCA1 stand-alone benign threshold. The variant is absent from gnomAD v4.1 and is present only once in gnomAD v2.1, far below the BA1 filter allele frequency threshold of greater than 0.1%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not meet the BRCA1 benign strong or supporting thresholds. The observed gnomAD v2.1 allele frequency of 3.98e-06 is below the BS1 supporting threshold of greater than 0.002%, and the variant is absent from gnomAD v4.1.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No qualifying observations in individuals without features of BRCA1/2-related Fanconi anemia were identified for this variant, so BS2 was not assessed.	cspec
BS3	Not met	Available functional and RNA evidence for this exact variant does not show a clearly normal effect. Instead, studies reported partial impact with retention of 8 nucleotides from intron 22, and the BRCA1 ENIGMA functional table indicates that BS3 is not met.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:30209399 PMID:31143303
BS4	Not assessed	No informative non-segregation dataset was identified for this variant, so BS4 was not assessed.	cspec
BP1	N/A	BP1 in this BRCA1 ENIGMA framework applies to silent, missense, or in-frame variants outside clinically important domains with no predicted splice effect. That rule does not fit this intronic splice-predictive variant.	cspec spliceai
BP2	N/A	BP2 is not used in this BRCA1 ENIGMA specification.	cspec
BP3	N/A	BP3 is not used in this BRCA1 ENIGMA specification.	cspec
BP4	Not met	Computational evidence does not support a benign interpretation. For intronic BRCA1 variants outside the native +/-1,2 splice sites, BP4 requires SpliceAI 0.10 or lower, but this variant has a SpliceAI maximum delta score of 1.00.	cspec spliceai
BP5	Not assessed	No usable benign-direction BRCA1 clinical-history likelihood ratio was identified for this variant, so BP5 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is not used in this BRCA1 ENIGMA specification.	cspec
BP7	Not met	Benign splice evidence is not supported. BP7_Supporting would require an intronic variant at or beyond +7/-21 together with BP4, and this variant is at c.5407-10 with SpliceAI 1.00, not BP4-compatible. RNA studies also showed abnormal splicing with retention of 8 intronic nucleotides, so BP7_Strong is not supported.	cspec spliceai vcep_specifications_table9_v1_2_2024_11_18 PMID:31143303

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.