Variant classification summary

NM_007294.4:c.19C>T

BRCA1 · NP_009225.1:p.(Arg7Cys) · NM_007294.4

GRCh37: chr17:41276095 G>A · GRCh38: chr17:43124078 G>A

Gene: BRCA1 Transcript: NM_007294.4

Final call

VUS

BS1 supporting benign

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Arg7Cys)

gnomAD AF

2.1694555534343102e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.4:c.19C>T (p.Arg7Cys) is a missense variant in exon 2 of BRCA1, within the RING domain (aa 2-101).

2

This variant is present at very low frequency in population databases: gnomAD v2.1 (6/251054 alleles, AF=2.39e-05) and gnomAD v4.1 (35/1613308 alleles, AF=2.17e-05), with no homozygotes observed.

3

The variant has been reported in ClinVar as Likely benign by 11 clinical laboratories and as Uncertain significance by 3 laboratories (ClinVar Variation ID: 37440, review status: criteria provided, single submitter).

4

ENIGMA Table9 classifies c.19C>T as 'None' (N/A) for both PS3 and BS3 due to discordant functional results: Findlay 2018 (PMID:30209399) reported no functional impact via saturation genome editing, while Bouwman 2020 (PMID:32546644) reported a deleterious effect via HRR complementation assay.

5

BayesDel no-AF score (0.021) falls below the PP3 threshold (≥0.28) and within the BP4 benign prediction range (≤0.15), but SpliceAI max delta (0.17) exceeds the BP4 threshold (≤0.1), precluding both PP3 and BP4 application under ENIGMA rules.

6

The Parsons et al. 2019 multifactorial likelihood analysis yielded a combined LR of 1.1146 (neutral zone), providing insufficient evidence for either PP4 or BP5.

7

The gnomAD v2.1 grpmax FAF of 2.299e-05 marginally exceeds the ENIGMA BS1_Supporting threshold (FAF > 0.00002), but the gnomAD v4.1 FAF of 1.884e-05 falls below this threshold. This borderline frequency evidence was applied as BS1_Supporting with a recommendation for human review.

8

No pathogenic evidence criteria are met. PVS1, PS1-PS5, PM1, PM2, PM5, PM6, PP1-PP5 are all not met or not applicable. The only criterion met is BS1 at supporting benign strength.

Final determination: ENIGMA Table 3: A single Supporting (Benign) criterion (BS1_Supporting) is insufficient for Likely Benign classification, which requires at minimum 2 Supporting (Benign) or 1 Strong (Benign) + 1 Supporting (Benign). No pathogenic criteria are met. The ENIGMA point-based scoring system yields -1 point (VUS range: -1 to 5). Final classification: VUS.

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	NM_007294.4:c.19C>T is a missense variant (p.Arg7Cys). PVS1 under the ENIGMA BRCA1 specification is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, single or multi-exon deletion). This missense substitution does not qualify.	pvs1_variant_assessment vcep_specifications_v1_2_2024_11_18
PS1	Not met	No previously classified pathogenic missense variant exists at amino acid position 7 (Arg7) to serve as a PS1 comparator. All sister variants at this position are classified as benign (BS3 per ENIGMA Table9: c.19C>G/p.Arg7Gly, c.20G>A/p.Arg7His, c.20G>C/p.Arg7Pro, c.20G>T/p.Arg7Leu) or indeterminate (c.19C>A/p.Arg7Ser, code None).	vcep_specifications_table9_v1_2_2024_11_18
PS2	N/A	PS2/PM6 de novo criteria are not applicable for BRCA1 under the ENIGMA v1.2 specification. BRCA1/2-related cancers occur relatively commonly; no information is available to calibrate the predictive capacity of de novo occurrences.	cspec
PS3	Not met	ENIGMA Table9 assigns code 'None' (N/A) for c.19C>T. Two calibrated functional studies produced discordant results: Findlay 2018 (PMID:30209399) classified the variant as functionally normal (FUNC), while Bouwman 2020 (PMID:32546644) classified it as deleterious. Per ENIGMA specification, discordant results from well-established assays preclude application of PS3.	vcep_specifications_table9_v1_2_2024_11_18 PMID:32546644
PS4	Not met	No case-control study demonstrates significantly increased prevalence of c.19C>T in affected individuals compared to controls. The ENIGMA PS4 threshold requires p≤0.05 and OR≥4 with lower confidence interval excluding 2.0. No such data are available in the case materials.
PS5	Not met	No previously classified pathogenic variant exists at amino acid position 7 (Arg7) with a different missense change. All sister missense variants at this position are classified as benign (BS3) or indeterminate (None) in ENIGMA Table9.	vcep_specifications_table9_v1_2_2024_11_18
PM1	N/A	PM1 is not applicable under the ENIGMA BRCA1 v1.2 specification. The CSPEC states PM1 is 'considered as component of bioinformatic analysis (PP3/BP4)' rather than applied independently. The variant's location in the RING domain (aa 2-101) is captured by PP3/BP4 bioinformatic assessment.	cspec
PM2	Not met	ENIGMA PM2_Supporting requires the variant to be absent from controls in gnomAD v2.1 and v3.1. NM_007294.4:c.19C>T is present in gnomAD v2.1 (6/251054 alleles, AF=2.39e-05) and gnomAD v4.1 (35/1613308 alleles, AF=2.17e-05). Presence in population databases precludes PM2 application.	gnomad_v2 gnomad_v4
PM5	N/A	ENIGMA repurposes PM5 specifically for protein termination codon (PTC) variants, as a complement to PVS1. NM_007294.4:c.19C>T is a missense variant (p.Arg7Cys), not a PTC. The pm5_candidates.json confirms classic same-residue missense PM5 is not applicable under this framework.	pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 de novo criteria are not applicable for BRCA1 under the ENIGMA v1.2 specification. BRCA1/2-related cancers occur relatively commonly; insufficient information exists to calibrate the predictive capacity of de novo occurrences.	cspec
PP1	Not met	No co-segregation data are available for NM_007294.4:c.19C>T. ENIGMA PP1 requires quantitative co-segregation analysis with LR≥2.08 for supporting, ≥4.3 for moderate, ≥18.7 for strong. No family studies or co-segregation LRs are present in the case materials.
PP2	N/A	PP2 (missense variant in a gene with low rate of benign missense variation) is not applicable under the ENIGMA BRCA1 v1.2 specification. The CSPEC marks PP2 applicability as Not Applicable.	cspec
PP3	Not met	The variant lies within the BRCA1 RING domain (aa 2-101), a clinically important functional domain. However, ENIGMA PP3 requires BayesDel no-AF score ≥0.28 for protein impact prediction, and SpliceAI ≥0.2 for splicing prediction. BayesDel for c.19C>T is 0.021 (far below 0.28 threshold). SpliceAI max delta is 0.17 (below 0.2 threshold). Neither bioinformatic threshold for PP3 is met.	bayesdel spliceai revel
PP4	Not met	The ENIGMA PP4 criterion captures combined multifactorial likelihood ratios toward pathogenicity. From the Parsons et al. 2019 (PMID:31131967) multifactorial analysis, c.19C>T has a combined LR of 1.1146, which falls in the neutral zone (>0.48 and <2.08) and does not meet the PP4_Supporting threshold of LR≥2.08. The variant was not listed in the Li et al. 2020 (PMID:31853058) clinical-history LR table. No other multifactorial data support pathogenicity.	vcep_humu_40_1557_s001 vcep_pmid_31853058_brca1_clinical_history_lr
PP5	N/A	PP5 is explicitly marked 'Not Applicable for this VCEP' by the ENIGMA BRCA1 specification v1.2. Furthermore, the ClinVar review status for this variant is 'criteria provided, single submitter' (1-star), which does not meet the global 3-star expert panel threshold for PP5 application.	cspec clinvar
BA1	Not met	ENIGMA BA1 (Stand Alone benign) requires a filter allele frequency (FAF) above 0.1% (FAF > 0.001). The maximum grpmax FAF for c.19C>T is 2.299e-05 (gnomAD v2.1) and 1.884e-05 (gnomAD v4.1), both several orders of magnitude below the 0.001 threshold.	gnomad_v2 gnomad_v4
BS1	Met	ENIGMA BS1_Supporting requires FAF > 0.002% (FAF > 0.00002) and ≤ 0.01% (≤ 0.0001). The gnomAD v2.1 grpmax FAF is 2.299e-05, which marginally exceeds the 0.00002 supporting threshold. However, gnomAD v4.1 grpmax FAF is 1.884e-05, which falls below the same threshold. Given the borderline nature and discrepancy between gnomAD versions, this call warrants human review. The variant has been observed in 6 alleles (v2.1) and 35 alleles (v4.1) with no homozygotes.	gnomad_v2 gnomad_v4
BS2	Not met	ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia phenotype, scored using the points system in ENIGMA Table 8. No proband-level data are available in the case materials to calculate BS2 points.
BS3	Not met	ENIGMA Table9 assigns code 'None' (N/A) for c.19C>T. Two calibrated functional studies produced discordant results: Findlay 2018 (PMID:30209399) classified the variant as functionally normal (FUNC), while Bouwman 2020 (PMID:32546644) classified it as deleterious. Per ENIGMA specification, discordant results from well-established assays preclude application of BS3.	vcep_specifications_table9_v1_2_2024_11_18 PMID:32546644
BS4	Not met	ENIGMA BS4 requires lack of segregation in affected family members as measured by a quantitative co-segregation analysis method. No segregation data or likelihood ratios are available for c.19C>T.
BP1	Not met	ENIGMA BP1_Strong applies to missense variants located OUTSIDE a clinically important functional domain AND with no splicing predicted (SpliceAI ≤0.1). c.19C>T (p.Arg7Cys) lies within the BRCA1 RING domain (aa 2-101), a clinically important functional domain. The variant does not qualify for BP1.	cspec
BP2	N/A	BP2 (observed in trans with a pathogenic variant for a fully penetrant dominant disorder) is not applicable under the ENIGMA BRCA1 v1.2 specification. The CSPEC marks BP2 applicability as Not Applicable.	cspec
BP3	N/A	BP3 (in-frame deletion/insertion in a repetitive region without known function) is not applicable for a missense substitution variant.
BP4	Not met	ENIGMA BP4_Supporting requires: inside a clinically important functional domain AND BayesDel ≤0.15 AND SpliceAI ≤0.1. c.19C>T is in the RING domain (qualifies) and BayesDel = 0.021 (≤0.15, qualifies), but SpliceAI max delta = 0.17 (>0.1, does not qualify). The SpliceAI score exceeds the BP4 threshold, precluding BP4 application.	bayesdel spliceai
BP5	Not met	ENIGMA BP5 captures combined multifactorial likelihood ratios against pathogenicity. From Parsons et al. 2019 (PMID:31131967), the combined LR for c.19C>T is 1.1146, falling in the neutral zone (>0.48 and <2.08). This does not meet the BP5_Supporting threshold of LR≤0.48. The variant was not present in the Li et al. 2020 clinical-history LR table.	vcep_humu_40_1557_s001 vcep_pmid_31853058_brca1_clinical_history_lr
BP6	N/A	BP6 is explicitly marked 'Not Applicable for this VCEP' by the ENIGMA BRCA1 specification v1.2. The ClinVar review status is 'criteria provided, single submitter' (1-star), which does not meet the global 3-star expert panel threshold for BP6 application.	cspec clinvar
BP7	N/A	ENIGMA BP7 applies to silent/intronic variants for splicing data, or to missense variants outside clinically important functional domains for RNA assay data. c.19C>T is a missense variant inside the RING domain (aa 2-101). For missense variants inside a functional domain, BS3 must be met for BP7_Strong(RNA) eligibility, which is not satisfied. BP7_Supporting is restricted to silent/intronic variants.	cspec

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