BRCA1 c.4797A>G, p.Ala1599=
NM_007294.4:c.4797A>G
Likely Benign
NM_007294.4:c.4797A>G is a synonymous BRCA1 variant with no predicted splicing impact, absent from population databases, and reported as Likely Benign in ClinVar. Application of PM2_Supporting, BP4_Supporting, BP6_Supporting, and BP7_Supporting yields a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
BP7
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.4797A>G
Protein Change
A1599=
Location
Exon 15
(Exon 15 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.4797A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Likely Benign
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (3 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies to null variants: "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 (LOF) is a known mechanism of disease." The evidence for this variant shows: NM_007294.4:c.4797A>G is a synonymous change, not predicted to abolish function or introduce a splice-site alteration. Therefore, this criterion is not applied because the variant is not a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a different nucleotide change results in the same amino acid change as a known pathogenic variant. The evidence shows: c.4797A>G is a synonymous change, not altering the amino acid. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies for de novo occurrence in a patient with confirmed parentage. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires well-established functional studies supportive of a damaging effect. The evidence shows: no functional assays have been performed on c.4797A>G. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 applies when prevalence in affected individuals is significantly increased (OR ≥4, p≤0.05). The evidence shows: no case–control or aggregate clinical data demonstrating enrichment. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants in established functional domains or mutational hotspots. The evidence shows: c.4797A>G is outside the BRCA1 RING, coiled-coil, and BRCT domains. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 Supporting: "Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer) and gnomAD v3.1 (non-cancer)." The evidence shows: c.4797A>G is not present in gnomAD or other population databases. Therefore, PM2 is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to recessive disorders with observed trans configuration. BRCA1 c.4797A>G is not in a recessive Fanconi anemia context. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels). The evidence shows: c.4797A>G is synonymous with no effect on protein length. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to novel missense changes at codons with known pathogenic missense variants. c.4797A>G is synonymous, not missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to presumed de novo cases without confirmation. No de novo information is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies for co-segregation with disease in multiple affected family members. No segregation data are available for this variant. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense rate. c.4797A>G is synonymous. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies to computational predictions of deleterious effect (BayesDel ≥0.28 or SpliceAI ≥0.2). The evidence shows: SpliceAI score 0.01 (no splicing impact) and no protein change. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies to specific clinical phenotype data contributing to pathogenicity. No phenotype data specific to this variant are available. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source classifies as pathogenic without available evidence. ClinVar classifies as Likely Benign, not pathogenic. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies when allele frequency >0.1%. The evidence shows: c.4797A>G is absent from population databases, not exceeding threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies when allele frequency >0.01%. The evidence shows: variant absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies in absence of recessive disease features (Fanconi anemia). No relevant homozygous or phenotypic data. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires well-established functional studies showing no damaging effect. No such studies exist for this variant. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies for lack of segregation in affected family members. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to missense variants outside functional domains. c.4797A>G is synonymous. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant co-occurs in trans with a pathogenic variant in a dominant gene. No such data exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. c.4797A>G is not an indel. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4 Supporting: "Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤0.15 AND SpliceAI ≤0.1)." The evidence shows: SpliceAI predicts no impact on splicing (score 0.01) and no amino acid change. Therefore, BP4 is applied at Supporting strength because multiple computational tools predict no impact.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies to co-observation with pathogenic variants in other genes without phenotype. No such co-occurrence data. Therefore, BP5 is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6: "Reputable source recently reports variant as benign, but the evidence is not available for independent evaluation." The evidence shows: ClinVar lists this variant as Likely Benign from three clinical laboratories. Therefore, BP6 is applied at Supporting strength.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, BP7: "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site." The evidence shows: SpliceAI score 0.01, no splice impact. Therefore, BP7 is applied at Supporting strength.