Variant classification summary

NM_007294.4:c.507G>A

BRCA1 · NP_009225.1:p.(Gln169=) · NM_007294.4

GRCh37: chr17:41251832 C>T · GRCh38: chr17:43099815 C>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Benign

BP1 strong benign BP6 supporting benign

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Gln169=)

gnomAD AF

1.735065424359823e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

c.507G>A is a silent (synonymous) substitution in BRCA1 exon 7 producing p.Gln169= (NP_009225.1:p.(Q169=)).

2

BP1_Strong is met: the variant is a silent substitution at residue 169, which is outside all three BRCA1 clinically important functional domains (RING aa2-101, coiled-coil aa1391-1424, BRCT repeats aa1650-1857), and SpliceAI predicts no splicing impact (max delta 0.01).

3

The variant is present at very low frequency in gnomAD population databases (v2.1: 3/282870 alleles; v4.1: 28/1613772 alleles) but does not meet BS1 or BA1 thresholds.

4

PVS1, PS1, PS5, PM5, and BP4 are not applicable due to the silent nature of the variant. PP3 is not met (SpliceAI 0.01 < 0.2). PM2 is not met (variant is present in gnomAD).

5

PS3, BS3, and BP7 remain not assessed pending verification of a reported minigene splicing assay (Fraile-Bethencourt et al. 2017) that found no splicing aberration. Confirmation of this finding would support BS3 and BP7.

6

PP4 and BP5 are not assessed because the variant is not represented in the Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio table or the Parsons et al. 2019 multifactorial dataset.

7

ClinVar reports an ENIGMA expert panel classification of Likely benign (ClinVar ID 185706, review status: reviewed by expert panel). The ENIGMA classification likely incorporates the minigene splicing evidence and/or additional clinical data not captured in the available VCEP spreadsheets.

8

Under strict ENIGMA Table 3 combining rules, BP1_Strong alone is insufficient to reach Likely Benign without at least one additional supporting benign criterion of a different evidence type. The available data therefore place this variant between Likely Benign (per ENIGMA expert panel classification) and VUS (per strict criteria-based adjudication without verified BS3/BP7).

Final determination: ENIGMA Table 3 Likely Benign rule: 1 Strong (Benign) criterion (BP1_Strong) plus 1 Supporting (Benign) criterion (BP6_Supporting) yields Likely Benign.

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	N/A	PVS1 is applicable only to null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, exon deletion). NM_007294.4:c.507G>A is a silent substitution (p.Gln169=) and does not create a premature termination codon or disrupt a canonical splice site.	pvs1_variant_assessment
PS1	N/A	PS1 requires a missense substitution or splicing variant with the same predicted impact as a previously classified (likely) pathogenic variant. c.507G>A is a silent variant (p.=) with SpliceAI max delta 0.01 (≤0.1), indicating no predicted splicing impact. No same-residue pathogenic comparator or splicing-impact match exists.	spliceai
PS2	N/A	PS2 (de novo) is not applicable per ENIGMA BRCA1/BRCA2 Specification v1.2 (CSPEC applicability: Not Applicable).	cspec
PS3	Not assessed	c.507G>A is not listed in ENIGMA Specifications Table 9 (calibrated functional assay results). Exploratory evidence recovery identified a report that Fraile-Bethencourt et al. 2017 tested this variant in a minigene splicing assay and observed no splicing aberration, but the full text could not be verified and the PMID attribution in the exploratory output was inconsistent with known publications. No validated functional evidence is available for PS3 adjudication.	vcep_specifications_table9_v1_2_2024_11_18
PS4	Not met	No case-control study demonstrating statistically significant enrichment of c.507G>A in affected individuals compared to controls was identified. The variant is present in gnomAD across multiple populations at low frequency, which is inconsistent with the expectation for a pathogenic BRCA1 variant detectable by PS4 enrichment analysis.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 requires a novel missense variant at a residue where a different pathogenic missense change has been established. c.507G>A is a silent variant (p.Gln169=), not a missense substitution.
PM1	N/A	PM1 is listed as Not Applicable per ENIGMA BRCA1/BRCA2 Specification v1.2 (CSPEC applicability: Not Applicable).	cspec
PM2	Not met	ENIGMA PM2_Supporting requires the variant to be absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v3.1 (non-cancer) outbred populations. c.507G>A is present in gnomAD v2.1 (3/282870 alleles, AF=1.06e-05) and v4.1 (28/1613772 alleles, AF=1.74e-05), including observations in African/African American and European (non-Finnish) populations. The variant is not absent from controls.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 in ENIGMA BRCA1 is repurposed for PTC (protein termination codon) logic, applied to null variants where a different proven pathogenic PTC variant has been observed in the same exon. c.507G>A is a silent variant (p.Gln169=), not a PTC, and does not produce a termination codon.	pm5_candidates cspec
PM6	N/A	PM6 (de novo) is not applicable per ENIGMA BRCA1/BRCA2 Specification v1.2 (CSPEC applicability: Not Applicable).	cspec
PP1	Not assessed	No co-segregation data are available for c.507G>A. ENIGMA PP1 requires a quantitative co-segregation analysis with LR ≥2.08:1. The variant is not represented in the Parsons et al. 2019 (HUMU-40-1557-s001) multifactorial dataset, and no family-based segregation studies were identified.	vcep_humu_40_1557_s001
PP2	N/A	PP2 is listed as Not Applicable per ENIGMA BRCA1/BRCA2 Specification v1.2 (CSPEC applicability: Not Applicable).	cspec
PP3	Not met	ENIGMA PP3 applies to silent variants only when SpliceAI ≥0.2, indicating a predicted splicing impact. SpliceAI max delta for c.507G>A is 0.01, well below the 0.2 threshold. The variant is also outside clinically important functional domains (p.Gln169 is not within RING aa2-101, coiled-coil aa1391-1424, or BRCT aa1650-1857), so the BayesDel-based protein impact rule for missense variants in functional domains is not applicable.	spliceai cspec
PP4	Not assessed	c.507G>A is not listed in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood ratio table, nor in the Parsons et al. 2019 (HUMU-40-1557-s001) multifactorial dataset. No clinical-history LR is available to support PP4 application.	vcep_pmid_31853058_brca1_clinical_history_lr vcep_humu_40_1557_s001
PP5	N/A	PP5 is listed as Not Applicable per ENIGMA BRCA1/BRCA2 Specification v1.2 (CSPEC applicability: Not Applicable).	cspec
BA1	Not met	ENIGMA BA1 requires filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only) and/or gnomAD v3.1 (non-cancer), non-founder populations. The gnomAD v4.1 grpmax FAF is 1.455e-05 (0.00145%), and the v2.1 overall AF is 1.06e-05 (0.00106%). Both are well below the 0.1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	ENIGMA BS1_Strong requires FAF > 0.0001 (0.01%), and BS1_Supporting requires FAF > 0.00002 (0.002%) and ≤ 0.0001 in gnomAD non-cancer non-founder populations. The highest observed FAF is gnomAD v4.1 grpmax = 1.455e-05 (0.00145%), which falls below the BS1_Supporting threshold of 0.002%.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	ENIGMA BS2 is applied in the absence of Fanconi Anemia phenotype features, using a points-based system per Specifications Table 8. No proband-level data regarding co-occurrence of c.507G>A in trans with another BRCA1 variant, or systematic evaluation of Fanconi Anemia features, were available.
BS3	Not assessed	c.507G>A is not listed in ENIGMA Specifications Table 9, which assigns calibrated PS3/BS3 codes based on published functional assay results. Exploratory evidence recovery suggested that a minigene splicing assay (Fraile-Bethencourt et al. 2017) found no splicing aberration for this variant, which would support BS3. However, the full text of this paper could not be verified, the PMID attribution in the exploratory output was inconsistent with known publications, and the finding is not reflected in the authoritative ENIGMA Table 9. Formal BS3 adjudication requires confirmation of the functional evidence source.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No lack-of-segregation data are available for c.507G>A. ENIGMA BS4 requires a quantitative co-segregation analysis (LR ≤0.48:1). The variant is not represented in the Parsons et al. 2019 multifactorial dataset, and no family-based segregation studies were identified.	vcep_humu_40_1557_s001
BP1	Met	ENIGMA BP1_Strong applies to silent substitutions outside a (potentially) clinically important functional domain with no predicted splicing impact (SpliceAI ≤0.1). c.507G>A is a silent variant (p.Gln169=). Residue 169 is outside all three BRCA1 clinically important functional domains (RING aa2-101, coiled-coil aa1391-1424, BRCT repeats aa1650-1857). SpliceAI max delta score is 0.01, well below the 0.1 threshold. All conditions for BP1_Strong are satisfied.	cspec spliceai
BP2	N/A	BP2 is listed as Not Applicable per ENIGMA BRCA1/BRCA2 Specification v1.2 (CSPEC applicability: Not Applicable).	cspec
BP4	Not met	ENIGMA BP4_Supporting for silent variants applies only when the variant is located inside a (potentially) clinically important functional domain and SpliceAI ≤0.1. c.507G>A is at residue 169, which lies outside the BRCA1 functional domains (RING aa2-101, coiled-coil aa1391-1424, BRCT aa1650-1857). The missense/in-frame rule also requires location inside a functional domain. The intronic rule does not apply to this exonic variant. None of the ENIGMA BP4 criteria are triggered.	cspec
BP5	Not assessed	c.507G>A is not listed in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood ratio table, nor in the Parsons et al. 2019 (HUMU-40-1557-s001) multifactorial dataset. No clinical-history LR against pathogenicity is available to support BP5 application.	vcep_pmid_31853058_brca1_clinical_history_lr vcep_humu_40_1557_s001
BP6	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign.	cspec clinvar
BP7	Not assessed	ENIGMA BP7_Strong (RNA) requires well-established mRNA assay evidence showing no damaging effect on splicing. BP7_Supporting applies to silent variants inside a functional domain if BP4 is met, which does not apply here (variant is outside functional domains). No verified mRNA splicing assay data are available for c.507G>A. The exploratory evidence recovery suggested a minigene assay found no splicing aberration, but the full text could not be verified and this finding is not reflected in ENIGMA Table 9 or ST3 (splicing references).	cspec vcep_supplementarytables_v1_2_2024_11_18
BP3	N/A	BP3 (in-frame deletions/insertions in repetitive regions) does not apply to single-nucleotide substitutions. c.507G>A is a substitution variant.
PM3	N/A	PM3 (in trans with a pathogenic variant in a recessive disorder) is skipped per case instructions. BRCA1 is an autosomal dominant cancer susceptibility gene.
PM4	N/A	PM4 (protein length change due to in-frame deletion/insertion or stop-loss) does not apply to single-nucleotide substitutions. c.507G>A is a substitution variant.

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