BRCA1 c.181T>G, p.Cys61Gly
NM_007294.3:c.181T>G
COSM9996592
Population Frequency
0.00319%
Low Frequency
ClinVar Classification
Pathogenic
16 publications
REVEL Score
0.948
Likely Pathogenic
COSMIC Recurrence
3 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
BRCA1
Transcript
NM_007294.4
MANE Select
Total Exons
23
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_007294.2 | Alternative | 23 exons | Reverse |
| NM_007294.3 | RefSeq Select | 23 exons | Reverse |
Variant Details
HGVS Notation
NM_007294.3:c.181T>G
Protein Change
C61G
Location
Exon 4
(Exon 4 of 23)
5'
Exon Structure (23 total)
3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 61: C61Y, C61R, C61S
Alternate Identifiers
COSM9996592
Variant interpretation based on transcript NM_007294.4
Clinical Evidence
Global Frequency
0.00319%
Rare
Highest in Population
European (non-Finnish)
0.00617%
Rare
Global: 0.00319%
European (non-Finnish): 0.00617%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 250754
Alt: 8
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00319%, 8/250754 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00617%, 7/113480 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
16 publications
Pathogenic
Based on 52 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
16 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as not provided (1 clinical laboratories) and as Pathogenic (52 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel.
Expert Panel Reviews
Pathogenic
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 61: C61Y, C61R, C61S
PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Functional Studies
Summary
The BRCA1 C61G variant has been functionally characterized and shown to have a damaging effect on BRCA1 function. It results in non-functional homologous recombination repair and is defective in the single-strand annealing pathway of double-strand break DNA repair. The variant disrupts binding to the E2 ubiquitin-conjugating enzyme UbcH5a and is associated with increased radiosensitivity, chromosomal instability, and other cellular abnormalities in vitro. These findings collectively suggest that the BRCA1 C61G mutation impairs the tumor suppressor function of BRCA1.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.948
0.948
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Benign:
CADD: 4.93
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant, BRCA1 c.181T>G (p.C61G), shows a missense change rather than a null variant. Therefore, this criterion is not applied because the variant type does not meet the PVS1 requirements.
PS1
PS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PS1 is applied when there is a different nucleotide change leading to the same amino acid change as a previously established pathogenic variant. The evidence for this variant does not provide such information. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PS2 is used for de novo variants with confirmed parentage. The evidence for this variant does not document any de novo occurrence. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines for BRCA1, PS3 is defined as: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect.' The provided functional evidence clearly states that the BRCA1 C61G variant disrupts binding to the E2 ubiquitin-conjugating enzyme and impairs multiple DNA repair pathways, leading to chromosomal instability. Therefore, this criterion is applied at Strong strength because the functional studies are well-established and supportive of pathogenicity.
PS4
PS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PS4 is used when the prevalence of the variant in affected individuals is significantly increased compared to controls. The evidence for this variant does not include case-control data that meet the necessary thresholds. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM1 is applied when the variant is located in a mutational hotspot or critical domain without benign variation. Although the variant lies within the RING domain of BRCA1, the available evidence did not specifically invoke PM1. Therefore, this criterion is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines for PM2, the rule is: 'Absent from controls (or present at an extremely low frequency in control populations).' The evidence shows a very low minor allele frequency of 0.00319% in gnomAD, indicating extreme rarity. Therefore, this criterion is applied at Supporting strength because the variant is essentially absent from control populations.
PM3
PM3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM3 is applied for recessive disorders when a variant is detected in trans with a pathogenic variant. Since BRCA1-related conditions follow an autosomal dominant pattern and there is no evidence of an in trans occurrence in a recessive context, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM4 is used for protein length changes due to in-frame deletions/insertions. The evidence for this variant indicates a missense change rather than an in-frame deletion/insertion. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, PM5 is defined as: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence indicates that this residue, C61, has previously been associated with pathogenicity through a different missense substitution. Therefore, PM5 is applied at Moderate strength due to the established significance of substitutions at this residue.
PM6
PM6 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM6 is applied for assumed de novo variants without confirmation. There is no evidence provided for a de novo occurrence of this variant. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PP1 is used for co-segregation evidence in families. The evidence provided does not include familial segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PP2 is applicable for genes with a low rate of benign missense variation where missense variants are a common mechanism of disease. Although BRCA1 is sensitive to missense changes, the evidence provided does not include additional data on missense constraint beyond what is captured by other criteria. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines for PP3, the rule is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product.' The evidence shows a REVEL score of 0.95, which is above the threshold of 0.75, indicating a strong computational prediction of a deleterious effect. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PP4 is used when the patient's phenotype is highly specific for a disease with a single genetic etiology. The evidence for this variant does not include detailed phenotypic data that exclusively support breast/ovarian cancer, so this criterion is not applied.
PP5
PP5 (Supporting)
According to Standard ACMG guidelines, PP5 is applied when a reputable source has reported the variant as pathogenic but the underlying evidence is not available for independent evaluation. The evidence indicates that multiple clinical laboratories and the ENIGMA expert panel have reported this variant as pathogenic in ClinVar. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BA1 is applied when the allele frequency in control populations is too high for the disorder. The evidence shows that the variant is extremely rare (MAF = 0.00319%), which does not meet the BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BS1 is applied when the allele frequency is above a defined threshold that argues against pathogenicity. The variant’s observed frequency is well below any such threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BS2 is used when there is evidence of the variant in healthy adult individuals with no signs of the disorder. There is no evidence provided indicating such observations; hence, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, BS3 is applied when well-established functional studies show no damaging effect on the gene product. The evidence for this variant, however, includes functional studies that demonstrate a damaging effect on BRCA1 function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BS4 is used when there is a lack of segregation with disease in family studies. The evidence for this variant does not include data that would support a lack of segregation. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP1 is applied when a missense variant is found in a gene for which primarily truncating variants cause disease. However, BRCA1 is known to have pathogenic missense variants in critical domains, and the variant in question affects a critical residue in the RING domain. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP2 is used when the variant is observed in trans with a pathogenic variant for a fully penetrant dominant disorder. There is no evidence provided for such an observation. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP3 is applied for in-frame deletions or insertions in repetitive regions without a functionally important role. The variant under evaluation is a missense change, so this criterion is not applicable.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines for BP4, the rule is: 'Missense or in-frame variants with multiple in silico tools predicting no impact on the gene or gene product.' The evidence for this variant demonstrates strong computational support for deleterious impact (REVEL score of 0.95). Therefore, BP4 is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP5 is applied when an alternate molecular cause for disease is present. The evidence for this variant does not support the presence of another cause; therefore, BP5 is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP6 is used when a reputable source reports the variant as benign, but the laboratory does not have access to the underlying data. In this case, reputable sources report pathogenicity. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP7 is applied to silent variants or intronic variants with no predicted impact on splicing. The variant in question is a missense variant and is predicted to alter protein function. Therefore, this criterion is not applied.