NM_007294.4:c.19C>T (p.Arg7Cys) is a missense variant in exon 2 of BRCA1, within the RING domain (aa 2-101). 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.1 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).2 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.3 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.4 The Parsons et al. 2019 multifactorial likelihood analysis yielded a combined LR of 1.1146 (neutral zone), providing insufficient evidence for either PP4 or BP5.5 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.6 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.
BRCA1
Final classification
VUS
BRCA1 c.19C>T · p.Arg7Cys
BRCA1
NM_007294.4:c.19C>T (p.Arg7Cys) is a missense variant in exon 2 of BRCA1, within the RING domain (aa 2-101).
Only one criterion met: BS1 at supporting benign strength (gnomAD v2.1 grpmax FAF 2.299e-05 marginally above the 0.00002 threshold, though v4.1 FAF 1.884e-05 falls below). ENIGMA Table 3 requires a minimum of 2 Supporting (Benign) or 1 Strong (Benign) + 1 Supporting (Benign) for Likely Benign. The ENIGMA point-based scoring system assigns -1 point, which falls in the VUS range (-1 to 5). No pathogenic criteria are met. The single borderline BS1_Supporting call is insufficient to reach any classification other than VUS.
Classification rationale
BS1
VUS
BRCA1 c.19C>T
BS1
→
VUS
3
vcep_specifications_table9_v1_2_2024_11_18PMID:32546644 ↗
4
bayesdelspliceai ↗
5
vcep_humu_40_1557_s001
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 14 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
supporting
review
Benign
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 v2.1 grpmax FAF: 2.299e-05 — above BS1_Supporting threshold of 0.00002.gnomAD v4.1 grpmax FAF: 1.884e-05 — below BS1_Supporting threshold.6/251054 alleles (v2.1)
Assessed · not applied
Pathogenic
PS1
No previously classified pathogenic missense variant exists at amino acid position 7 (Arg7) to serve as a PS1 comparator.
PS3
ENIGMA Table9 assigns code 'None' (N/A) for c.19C>T.
PS4
No case-control study demonstrates significantly increased prevalence of c.19C>T in affected individuals compared to controls.
PM2
ENIGMA PM2_Supporting requires the variant to be absent from controls in gnomAD v2.1 and v3.1.
PP1
No co-segregation data are available for NM_007294.4:c.19C>T.
PP3
The variant lies within the BRCA1 RING domain (aa 2-101), a clinically important functional domain.
PP4
The ENIGMA PP4 criterion captures combined multifactorial likelihood ratios toward pathogenicity.
Benign
BA1
ENIGMA BA1 (Stand Alone benign) requires a filter allele frequency (FAF) above 0.1% (FAF > 0.001).
BS2
ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia phenotype, scored using the points system in ENIGMA Table 8.
BS3
ENIGMA Table9 assigns code 'None' (N/A) for c.19C>T.
BS4
ENIGMA BS4 requires lack of segregation in affected family members as measured by a quantitative co-segregation analysis method.
BP1
ENIGMA BP1_Strong applies to missense variants located OUTSIDE a clinically important functional domain AND with no splicing predicted (SpliceAI ≤0.1).
BP4
ENIGMA BP4_Supporting requires: inside a clinically important functional domain AND BayesDel ≤0.15 AND SpliceAI ≤0.1.
BP5
ENIGMA BP5 captures combined multifactorial likelihood ratios against pathogenicity.
N/A · 11
PVS1 · PS2 · PM1 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.16946e-05; MAF= 0.00217%, 35/1613308 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164636; MAF= 0.01646%, 1/6074 alleles, homozygotes = 0); grpmax FAF= 1.884e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 2.38992e-05; MAF= 0.00239%, 6/251054 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.2925e-05; MAF= 0.00529%, 6/113368 alleles, homozygotes = 0); grpmax FAF= 2.299e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0022%
· 35 / 1,613,308
0 hom · FAF 0.0019%
0 hom · FAF 0.0019%
Middle Eastern 1 / 6,074 |
0.016% |
European (non-Finnish) 31 / 1,179,452 |
0.0026% |
East Asian 1 / 44,850 |
0.0022% |
Remaining individuals 1 / 62,452 |
0.0016% |
South Asian 1 / 91,076 |
0.0011% |
+ 5 not observed (Admixed American, European (Finnish), Amish, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0024%
· 6 / 251,054
0 hom · FAF 0.0023%
0 hom · FAF 0.0023%
European (non-Finnish) 6 / 113,368 |
0.0053% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 37440)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). REVEL score = 0.558. BayesDel score = 0.0211131.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV100524047, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 9 PMIDs not cited in assessment
16267036 ↗
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.
CLINVAR
16403807 ↗
Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
32546644 ↗
Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays.
CLINVAR
35659930 ↗
Comprehensive evaluation and efficient classification of BRCA1 RING domain missense substitutions.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR