Variant classification summary

NM_007294.4:c.3170G>A

BRCA1 · NP_009225.1:p.(Ser1057Asn) · NM_007294.4

GRCh37: chr17:41244378 C>T · GRCh38: chr17:43092361 C>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

VUS

BP1 strong

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Ser1057Asn)

gnomAD AF

1.8588235877277989e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

c.3170G>A (p.Ser1057Asn) is a missense variant in BRCA1 exon 10 (legacy exon 11) located at amino acid position 1057, outside the established clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857).

2

SpliceAI predicts no splicing impact (max delta score 0.00), and BayesDel no-AF score is -0.0291, consistent with a benign computational prediction.

3

BP1_Strong is met: the variant is a missense substitution outside clinically important functional domains with no predicted splicing impact (SpliceAI ≤0.1). This is the only applicable ACMG/AMP criterion supported by current evidence.

4

BRCA1 exon 11 (aa 224-1366), where p.Ser1057Asn resides, has been characterized as a coldspot with zero pathogenic or likely pathogenic missense variants among 1,117 exon 11 missense variants reported to ClinVar.

5

The variant is present at extremely low frequency in population databases (gnomAD v2.1: 1/250,824 alleles, AF=0.0004%; gnomAD v4.1: 3/1,613,924 alleles, grpmax FAF=6.8e-7), below thresholds for both benign (BS1) and pathogenic (PM2) population criteria.

6

No functional data, case-control studies, segregation analysis, clinical history likelihood ratios, or variant-specific publications were identified for this variant. It is reported in ClinVar as Uncertain Significance (5 clinical laboratories, single submitter criteria only, no expert panel review).

7

Under the ENIGMA BRCA1 v1.2 point-based classification system, the evidence totals -4 points (BP1_Strong alone), placing the variant in the Likely Benign range (-6 to -2). However, ENIGMA Table 3 requires multiple evidence types to support Likely Benign when based on a single Strong Benign criterion. With only BP1_Strong met and no additional benign criteria satisfied from independent evidence types, the classification defaults to Uncertain Significance per the ENIGMA adapted ACMG/AMP framework.

Final determination: ENIGMA BRCA1 v1.2 Table 3: a single Strong Benign criterion (BP1_Strong) does not satisfy any Likely Benign combination rule because the 1-Strong-Benign-alone rule requires multiple independent evidence types, and no other benign criteria are met; the variant therefore defaults to Uncertain Significance.

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 not applicable to missense variants. NM_007294.4:c.3170G>A is a missense substitution (p.Ser1057Asn), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). ENIGMA BRCA1 PVS1 rules apply only to null variants per Specifications Table 4.	pvs1_generic_framework vcep_specifications_table4_v1_2_2024_11_18
PS1	Not met	No previously classified pathogenic or likely pathogenic missense variant was identified at the same amino acid residue (Ser1057) in ClinVar or ENIGMA reference datasets. ENIGMA PS1 requires a same-residue pathogenic comparator with the same predicted impact on protein or splicing, which is not available for this variant.	clinvar vcep_supplementarytables_v1_2_2024_11_18
PS2	N/A	ENIGMA BRCA1 VCEP marks PS2 (de novo) as Not Applicable. BRCA1/2-related cancers occur relatively commonly and de novo occurrence data cannot be calibrated for these genes.	cspec
PS3	Not met	c.3170G>A (p.Ser1057Asn) is not listed in ENIGMA Table 9 curated functional assay results and is not present in Supplementary Table 4 functional assay data. No variant-specific functional studies demonstrating a damaging effect were identified in the reviewed literature. The variant falls within BRCA1 exon 11 spacer region (aa 224-1366), which is outside the established clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857).	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 oncokb
PS4	Not assessed	No case-control data are available for this variant. ENIGMA PS4 requires case-control studies with p≤0.05 and OR≥4 (lower CI excludes 2.0). No such study was identified in the case materials or literature.
PS5	N/A	PS5 is not a standard ACMG/AMP evidence criterion and is not defined in the ENIGMA BRCA1 VCEP specifications version 1.2. No applicable rule exists for this code.	cspec
PM1	N/A	ENIGMA BRCA1 VCEP marks PM1 as Not Applicable. The criterion is considered as a component of the bioinformatic analysis under PP3/BP4. Domain-level assessment is integrated into those codes rather than applied as a standalone PM1.	cspec
PM2	Not met	ENIGMA PM2_Supporting requires the variant to be absent from gnomAD v2.1 (non-cancer, exome) and v3.1 (non-cancer) in outbred populations. This variant is present in gnomAD v2.1 (1/250824 alleles, AF=3.99e-6) and gnomAD v4.1 (3/1613924 alleles, AF=1.86e-6). Per ENIGMA guidance, observation even once in an outbred population is not informative for PM2 and the criterion does not apply.	gnomad_v2 gnomad_v4
PM5	N/A	ENIGMA BRCA1 repurposes PM5 for protein termination codon (PTC) variants in exons where a proven pathogenic PTC variant has been observed (PM5_PTC). c.3170G>A is a missense variant, not a PTC variant. Classic same-residue missense PM5 is not applicable in the ENIGMA framework for BRCA1.	vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	ENIGMA BRCA1 VCEP marks PM6 (assumed de novo) as Not Applicable. BRCA1/2-related cancers occur relatively commonly, and there is insufficient information to calibrate the predictive capacity of de novo occurrences for these genes.	cspec
PP1	Not assessed	No co-segregation data are available for this variant. ENIGMA PP1 requires quantitative co-segregation analysis with LR≥2.08. No segregation data were identified in the case materials or reviewed literature.
PP2	N/A	ENIGMA BRCA1 VCEP marks PP2 as Not Applicable.	cspec
PP3	Not met	ENIGMA PP3 for missense variants requires the variant to be located inside a clinically important functional domain with BayesDel ≥0.28, or SpliceAI ≥0.2 for splicing prediction. p.Ser1057Asn is at amino acid position 1057, which lies outside the established BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). BayesDel score is -0.0291 (<0.28) and SpliceAI max delta is 0.0 (<0.2). Neither protein-level nor splicing-level PP3 conditions are satisfied.	bayesdel spliceai revel cspec
PP4	Not assessed	ENIGMA PP4 requires calibrated clinical history likelihood ratio data (LR≥2.08). The variant c.3170G>A is not present in the Li et al. 2020 (PMID:31853058) BRCA1 clinical history LR table, and is not listed in the Parsons et al. 2019 (PMID:31131967) multifactorial likelihood dataset. No clinical history LR toward pathogenicity is available.	vcep_pmid_31853058_brca1_clinical_history_lr vcep_humu_40_1557_s001
PP5	N/A	ENIGMA BRCA1 VCEP marks PP5 as Not Applicable per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. This criterion is not for use in this VCEP framework.	cspec
BA1	Not met	BA1 requires filter allele frequency (FAF) > 0.1% (0.001) in gnomAD non-cancer, non-founder populations. The variant's maximum FAF is 6.8e-7 (gnomAD v4.1 grpmax), far below the BA1 threshold of 0.001. This variant is extremely rare in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	ENIGMA BS1_Strong requires FAF > 0.01% (0.0001) and BS1_Supporting requires FAF > 0.002% (0.00002). The variant's highest FAF is 8.83e-6 in gnomAD v2.1 NFE (0.00088%), which is below even the BS1_Supporting threshold of 0.00002 (0.002%). The variant is too rare to satisfy BS1 at any strength.	gnomad_v2 gnomad_v4
BS2	Not assessed	ENIGMA BS2 requires co-observation data in the absence of Fanconi Anemia phenotype features, with point-based scoring per proband. No co-observation data for this variant were identified in the case materials or literature.
BS3	Not met	c.3170G>A (p.Ser1057Asn) is not listed in ENIGMA Table 9 with a BS3 assignment and is not present in Supplementary Table 4 functional assay results with an outcome of no functional impact. No variant-specific functional studies demonstrating a neutral or non-damaging effect were identified in the reviewed literature.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	ENIGMA BS4 requires lack of segregation in affected family members, measured by quantitative co-segregation analysis (LR≤0.48). No segregation data for this variant were identified.
BP1	Met	ENIGMA BP1_Strong applies to missense variants located outside the clinically important functional domains of BRCA1 when no splicing is predicted. p.Ser1057Asn is at amino acid position 1057, which lies in the exon 11 spacer region (aa 224-1366), well outside the RING domain (aa 2-101), coiled-coil domain (aa 1391-1424), and BRCT repeats (aa 1650-1857). SpliceAI max delta score is 0.0, confirming no predicted splicing impact. This region has been characterized as a coldspot with zero pathogenic/likely pathogenic missense variants among 1,117 exon 11 missense variants in ClinVar (Dines et al. 2020, PMID:31911673).	spliceai cspec PMID:31911673 vcep_appendices_v1_2_2024_11_18
BP2	N/A	ENIGMA BRCA1 VCEP marks BP2 as Not Applicable. This criterion is applied only in the context of BS2, which is not assessed here.	cspec
BP4	Not met	ENIGMA BP4 for missense variants requires the variant to be located inside a clinically important functional domain AND have no predicted impact (BayesDel ≤0.15 AND SpliceAI ≤0.1). While the BayesDel score (-0.0291) and SpliceAI (0.0) satisfy the prediction thresholds, the variant is located at aa 1057, outside the defined BRCA1 functional domains (RING 2-101, coiled-coil 1391-1424, BRCT 1650-1857). The domain-location condition for BP4 is not met.	bayesdel spliceai cspec
BP5	Not assessed	ENIGMA BP5 requires calibrated clinical history likelihood ratio data toward benignity (LR≤0.48). The variant c.3170G>A is not present in the Li et al. 2020 (PMID:31853058) BRCA1 clinical history LR table and is not listed in the Parsons et al. 2019 (PMID:31131967) multifactorial dataset. No LR toward benignity is available.	vcep_pmid_31853058_brca1_clinical_history_lr vcep_humu_40_1557_s001
BP6	N/A	ENIGMA BRCA1 VCEP marks BP6 as Not Applicable per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. This criterion is not for use in this VCEP framework.	cspec
BP7	Not met	ENIGMA BP7_Strong (RNA) for missense variants outside functional domains requires well-established mRNA assay data demonstrating no splicing impact. No mRNA transcript analysis data are available for c.3170G>A. BP7_Supporting applies only to silent or intronic variants, not missense. Although SpliceAI predicts no splicing impact (delta=0.0), ENIGMA requires direct experimental mRNA evidence for BP7 application to missense variants.	spliceai cspec

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