BRCA1 c.5278-22C>T, p.?
NM_007294.4:c.5278-22C>T
Likely Benign
This intronic variant is beyond canonical splice sites, has no predicted splicing impact, and exceeds the BA1 frequency threshold in gnomAD. Reputable source data further support benign classification. BA1 stand-alone suffices to classify the variant as Benign.
ACMG/AMP Criteria Applied
BA1
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.5278-22C>T
Protein Change
?
Location
Exon 19
(Exon 19 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.5278-22C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0252%
Low Frequency
Highest in Population
Admixed American
0.201%
Common
Global: 0.0252%
Admixed American: 0.201%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282218Alt: 71Homozygotes: 1
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0252%, 71/282218 alleles, homozygotes = 1) and at a higher frequency in the Admixed American population (MAF= 0.201%, 71/35392 alleles, homozygotes = 1). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 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 (2 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 only to null variants in a gene where loss of function is a known mechanism. The rule for PVS1 is: "Very Strong Null variant (nonsense, frameshift, splice site (+/−1,2), initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease." The evidence for this variant shows it is an intronic change at position -22, outside canonical splice sites. Therefore, this criterion is not applied at any strength because the variant does not create a null allele.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 applies when a variant results in the same amino acid change as a known pathogenic variant. The rule is: "Strong: Same amino acid change as a previously established pathogenic variant." The evidence for this variant shows it is intronic with no protein change. Therefore, this criterion is not applied because there is no amino acid alteration.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies for de novo variants with confirmed paternity and maternity. The rule is: "Strong: De novo (both maternity and paternity confirmed)." There is no evidence of de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 applies when well-established functional studies show a damaging effect. The rule is: "Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect." No functional assay data exist for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 applies when case-control data show a significant increase in affected individuals (OR ≥4, p ≤0.05). No case-control or cohort data are available for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants located in mutational hot spots or critical functional domains without benign variation. The rule is: "Moderate: Located in a mutational hot spot and/or critical functional domain." This variant is intronic and outside defined functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, PM2 supports absence from controls. The rule is: "Supporting: Absent from controls in gnomAD v2.1 and v3.1 (read depth ≥25)." The evidence shows the variant is present in gnomAD (MAF=0.0252%, 71/282,218 alleles). Therefore, this criterion is not applied because the variant is not absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies for recessive Fanconi anemia phenotypes with variants in trans. The rule is: "Supporting/Moderate/Strong based on points for trans configuration in a compatible phenotype." There is no evidence of this variant occurring in trans in a recessive phenotype. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels or stop-loss). The rule is: "Moderate: Protein length changes due to in-frame deletions/insertions or stop-loss variants." This variant is intronic and does not change protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 applies to novel missense changes at residues where other pathogenic missense changes have been observed. The rule is: "Moderate: Novel missense at amino acid residue where a different pathogenic missense has been seen." This variant is intronic. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to unconfirmed de novo variants. The rule is: "Moderate: De novo (without confirmation of paternity/maternity)." There is no evidence of de novo occurrence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies to co-segregation with disease. The rule is: "Supporting/Moderate/Strong based on LOD score or Bayes factor for segregation in affected family members." No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low rate of benign missense changes. The rule is: "Supporting: Missense in a gene with a low rate of benign missense variants." This variant is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies to variants predicted to impact splicing or protein function. The rule is: "Supporting: Predicted splicing impact (SpliceAI ≥0.2) or protein impact (BayesDel ≥0.28) inside key domains." SpliceAI predicts no impact (score=0). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies to well‐characterized phenotypes in multifactorial likelihood models. The rule is: "Supporting/Moderate/Strong based on combined LR from clinical data for highly specific phenotype." No patient phenotype data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source reports the variant as pathogenic without underlying evidence. The rule is: "Supporting: Reputable source reports pathogenic." No source reports pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Stand Alone) Strength Modified
According to VCEP guidelines, BA1 is met when the FAF is above 0.1%. The rule is: "Stand Alone: Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD non-cancer populations." The evidence shows the variant has an Admixed American population MAF of 0.201% (>0.1%). Therefore, this criterion is applied at Stand Alone strength because the allele frequency exceeds the BA1 threshold.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 is met when FAF >0.01% (FAF >0.0001). The rule is: "Strong: Filter allele frequency >0.01%." Although the variant’s FAF of 0.201% exceeds this threshold, BA1 Stand Alone has already been applied and supersedes BS1. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies in the absence of recessive disease features (e.g., Fanconi Anemia). The rule is: "Supporting/Moderate/Strong based on absence of recessive phenotype points." No phenotype data indicating absence or presence of FA are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies when functional studies show no damaging effect. The rule is: "Strong: Well-established functional studies show no damaging effect on protein or transcript." No such assays exist for this variant. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies to lack of segregation in affected family members. The rule is: "Supporting/Moderate/Strong based on Bayes score for non‐segregation." No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to silent or missense variants outside key domains with no splicing impact. The rule is: "Strong: Silent/missense outside functional domains and SpliceAI ≤0.1." This variant is intronic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when a variant is observed in trans with a pathogenic variant for a dominant disorder or in cis for a recessive disorder. The rule is: "Supporting: Co-occurrence with a pathogenic variant in trans (dominant) or in cis (recessive)." No such co-occurrence data exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive, low-complexity regions. The rule is: "Supporting: In-frame indel in repetitive region with no known function." This variant is intronic and not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4 applies to intronic variants outside donor/acceptor sites with no predicted splicing impact. The rule is: "Supporting: Intronic variants outside ±1,2 and SpliceAI ≤0.1." The evidence shows the variant is at -22 and SpliceAI score=0. Therefore, this criterion is applied at Supporting strength because computational evidence predicts no splicing effect.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 captures combined LR against pathogenicity from multifactorial clinical data in cases with other pathogenic variants. The rule is: "Supporting/Moderate/Strong based on combined clinical LR against pathogenicity." No co-occurrence or multifactorial data are available. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6 applies when a reputable source reports the variant as benign without underlying evidence. The rule is: "Supporting: Reputable source reports benign." ClinVar reports this variant as Likely benign from two clinical laboratories. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Supporting)
According to VCEP guidelines, BP7 applies to intronic variants outside conserved motif positions (beyond ±1,2 and at or beyond ±7/−21) if BP4 is met. The rule is: "Supporting: Intronic variants at or beyond positions +7/−21 with BP4 met." The variant is at -22 and BP4 is met. Therefore, this criterion is applied at Supporting strength.