BRCA1 c.3143G>A, p.Gly1048Asp
NM_007294.4:c.3143G>A
Variant of Uncertain Significance (VUS)
NM_007294.4:c.3143G>A (p.G1048D) in BRCA1 is a rare missense variant with PM2_Supporting (absent/very rare) and BP1_Strong (out-of-domain missense with no splicing impact). No additional pathogenic or benign criteria are met; the conflicting evidence supports a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP1
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_007294.4:c.3143G>A
Protein Change
G1048D
Location
Exon 10
(Exon 10 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1048 in gene BRCA1
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.3143G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00319%
Rare
Highest in Population
African/African American
0.0361%
Low Frequency
Global: 0.00319%
African/African American: 0.0361%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282390Alt: 9Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00319%, 9/282390 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.0361%, 9/24962 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
7 publications
Uncertain Significance (VUS)
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
5 VUS
4 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (7)
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
This missense variant replaces glycine with aspartic acid at codon 1048 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in breast, pancreatic and prostate cancer case-control studies in 1 unaffected individual per study and absent in cancer cases (PMID: 30287823, 31214711, 32980694) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.1391 and 0.4042, respectively (PMID: 31131967). This variant has been identified in 9/282390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Variant summary: BRCA1 c.3143G>A (p.Gly1048Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consistent with these predictions, this missense variant lies in the coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). The variant allele was found at a frequency of 3.6e-05 in 356168 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (3.6e-05 vs 0.001), allowing no conclusion about variant significance. c.3143G>A has been observed in individuals affected with breast and/or ovarian cancer (e.g., Judkins_2005, Anczukow_2008, Guindalini_2020) as well as in unaffected controls (e.g., Momozawa_2018, Mizukami_2020, Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Anczukow_2008). Recent reports from the CAGI5 ENIGMA challenge have classified this variant as likely benign (Cline_2019, Padilla_2019). The following publications have been ascertained in the context of this evaluation (PMID: 35264596, 36243179, 31112341, 18273839, 31294896, 16267036, 25011685, 30287823, 15385441, 23893897, 32980694, 31911673). ClinVar contains an entry for this variant (Variation ID: 54776). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratories) and as Uncertain Significance (1 clinical laboratories).
Functional Impact
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
No evidence of other pathogenic variants at position 1048 in gene BRCA1
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.391
0.391
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.33polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor ±1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: NM_007294.4:c.3143G>A is a missense change (G1048D), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Apply PS1 for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI ≤0.1))." The evidence for this variant shows: there is no previously established pathogenic variant producing the same amino acid change at p.G1048. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: there is no reported de novo occurrence. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows: no functional assay data are available for p.G1048D. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (p-value ≤0.05 and OR ≥4)." The evidence for this variant shows: no case-control or affected-individual data reported. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: p.G1048 lies outside the defined BRCA1 RING, coiled-coil, and BRCT domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer) and gnomAD v3.1 (non-cancer)." The evidence for this variant shows: MAF=0.00319% in gnomAD non-cancer exomes, meeting absence/very rarity. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Apply for patient with phenotype consistent with BRCA1-related Fanconi Anemia and co-occurent variants in the same gene." The evidence for this variant shows: no Fanconi Anemia phenotype or trans variants reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: this is a missense substitution with no protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows: no other pathogenic missense at residue Gly1048 is reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members measured by quantitative analysis." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease." The evidence for this variant shows: BRCA1 has many missense VUS and a mixed mechanism; no specific data support PP2. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Apply PP3 for missense or in-frame variants inside a clinically important functional domain and predicted impact via protein change (BayesDel no-AF ≥0.28) or SpliceAI ≥0.2 for splicing." The evidence for this variant shows: p.G1048D lies outside defined domains and SpliceAI=0.02 (<0.2). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Combined clinical evidence (multifactorial likelihood) for breast cancer features." The evidence for this variant shows: no such clinical likelihood data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic." The evidence for this variant shows: ClinVar submissions are conflicting and none conclusively pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Filter allele frequency >0.1% in gnomAD non-cancer." The evidence for this variant shows: MAF=0.00319% <0.1%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Filter allele frequency >0.01% in gnomAD non-cancer." The evidence for this variant shows: MAF=0.00319% <0.01%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Applied in absence of recessive Fanconi Anemia features." The evidence for this variant shows: no healthy adult observation data in unaffected carriers. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Well-established functional studies show no damaging effect." The evidence for this variant shows: no functional assay data demonstrating no effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Lack of segregation in affected family members." The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Strong Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)." The evidence for this variant shows: p.G1048D is a missense change at aa1048 (outside RING 2–101, coiled-coil 1391–1424, BRCT 1650–1857) and SpliceAI predicts 0.02 (≤0.1). Therefore, this criterion is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in a repetitive region without a known function." The evidence for this variant shows: this is a missense substitution, not applicable. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Missense or in-frame variants inside a clinically important functional domain with no predicted impact (BayesDel no-AF ≤0.15 AND SpliceAI ≤0.1)." The evidence for this variant shows: p.G1048D lies outside those domains. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Combined clinical evidence against pathogenicity based on multifactorial likelihood." The evidence for this variant shows: no such multifactorial data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without available evidence." The evidence for this variant shows: ClinVar entries are conflicting and not solely benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Silent variant inside a clinically important functional domain or intronic outside conserved sites with no predicted splicing impact if BP4 met." The evidence for this variant shows: this is a missense change and BP4 is not met. Therefore, this criterion is not applied.