BRCA1 c.1724A>G, p.Glu575Gly
NM_007294.4:c.1724A>G
Variant of Uncertain Significance (VUS)
The final classification of BRCA1 c.1724A>G (p.E575G) remains as a Variant of Uncertain Significance (VUS) due to the application of two moderate pathogenic criteria (PM2 and PM5) offset by supporting benign evidence (BP4), with insufficient and conflicting evidence across other criteria. No additional criteria could be evaluated to resolve the uncertainty.
ACMG/AMP Criteria Applied
PM2
PM5
BP4
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.1724A>G
Protein Change
E575G
Location
Exon 10
(Exon 10 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 575: E575K
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.1724A>G
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Clinical Data
Global Frequency
0.00199%
Rare
Highest in Population
African/African American
0.0246%
Low Frequency
Global: 0.00199%
African/African American: 0.0246%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250754Alt: 5Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00199%, 5/250754 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.0246%, 4/16242 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
5 publications
Uncertain Significance (VUS)
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
5 VUS
3 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (5)
Variant summary: BRCA1 c.1724A>G (p.Glu575Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-05 in 1613682 control chromosomes, predominantly at a frequency of 0.00033 within the African or African-American subpopulation in the gnomAD v4.0.0 database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00033 vs 0.001). However, the variant was also reported from the southern part of Africa with an even higher allele frequency, i.e. 0.029 (6/208 alleles), including 1 homozygote (in the GenomeAsia 100K database). In addition, it was found in 1/ 2559 African American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). These data suggest that the variant could be a benign polymorphism. The variant, c.1724A>G, has been reported in the literature in individuals with a personal of family history of Hereditary Breast And Ovarian Cancer Syndrome (e.g., Combrink_2021, Ren_2021, Hovland_2022, Gifoni_2022), however without strong evidence for causality (e.g., lack of co-segregation data). It has also been reported in the BRCA Share database (formerly UMD-BRCA1) in one proband (without co-occurrence with other deleterious variants in BRCA1/2). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34218100, 35957908, 21702907, 34981296, 25348012, 34196900). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=4) or benign/likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
The BRCA1 c.1724A>G (p.Glu575Gly) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 35957908 (2022), 35464868 (2022) 34196900 (2021), 34218100 (2021)). Additionally, this variant has been reported to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.00025 (4/16242 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
This missense variant replaces glutamic acid with glycine at codon 575 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with breast cancer (PMID: 34196900, 34218100) and in one individual age 70 years or older without cancer by FLOSSIES (https://whi.color.com/variant/17-41245824-T-C). This variant has been identified in 5/250754 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.
This missense variant replaces glutamic acid with glycine at codon 575 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with breast cancer (PMID: 34196900, 34218100) and in one individual age 70 years or older without cancer by FLOSSIES (https://whi.color.com/variant/17-41245824-T-C). This variant has been identified in 5/250754 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.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Uncertain significance (5 clinical laboratories) and as Uncertain Significance (1 clinical laboratories) and as Benign (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
ClinVar reports other pathogenic variants at position 575: E575K
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.369
0.369
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
Pathogenic:
metasvm: Dmetalr: D
Benign:
CADD: 0.98polyphen_prediction: benignprimateai: T
Neutral: Show all
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 (nonsense, frameshift, splice site ±1/2, initiation codon, or multi‐exon deletions) in genes where loss of function is a known disease mechanism. The rule states: 'Null Variant in a gene where LOF is a known mechanism.' The evidence for this variant (BRCA1 c.1724A>G; p.E575G) is a missense change, not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 is applied when the variant results in the same amino acid change as a previously established pathogenic variant despite a different nucleotide change. The rule states: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows that the change is novel and no such identical amino acid change has been established as pathogenic. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies when there is de novo occurrence (with confirmed maternity and paternity) in a patient with the disease and no family history. The rule states: 'De novo (both maternity and paternity confirmed) in a patient with the disease.' There is no evidence of a de novo occurrence for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing guidelines for PS3, the rule requires well‐established in vitro or in vivo functional studies supportive of a damaging effect on protein function. The note states: 'The BRCA1 E575G variant has not been functionally characterized, and its biological significance remains unknown.' The evidence shows no conclusive functional impact. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 is applied when the prevalence of the variant in affected individuals is significantly increased compared to controls (with a case‐control study p-value ≤ 0.05 and OR ≥4). The rule states: 'Prevalence significantly increased in affected individuals.' There is no such case-control data provided for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 is applied when a variant is located in a mutational hot spot or a critical and well-established functional domain without benign variation. The rule states: 'Located in a mutational hot spot and/or critical functional domain.' The evidence does not indicate that the affected residue (E575) is within such a domain, nor is there any additional hotspot information. Therefore, PM1 is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines (and consistent with VCEP modifications for BRCA1), PM2 is applied when a variant is absent or present at an extremely low frequency in large population databases. The rule states: 'Absent from controls (or at extremely low frequency if recessive) in large population datasets.' The evidence shows a MAF of 0.00199% in gnomAD and slightly higher frequency in the African/African American population, which qualifies as extremely rare; hence, PM2 is applied at moderate strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 is used for recessive disorders when there is evidence of a variant in trans with a pathogenic variant. The rule states: 'Detected in trans with a pathogenic variant in a recessive disorder.' Since BRCA1 is associated with dominant cancer predisposition and there is no evidence of a second variant or recessive inheritance pattern, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 is applied for protein length changes due to in-frame deletions/insertions in non-repetitive regions. The rule states: 'In-frame deletion/insertion or stop-loss variants that result in a protein length change.' The variant in question is a missense change and does not result in a protein length change. Therefore, PM4 is not applied.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, PM5 is used when a novel missense change occurs at an amino acid residue where a different missense change determined to be pathogenic has been observed. The rule states: '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 is a novel missense change (E575G) at a residue where another pathogenic missense variant has been reported. Therefore, PM5 is applied at moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 is applied for assumed de novo variants without confirmation. The rule states: 'Assumed de novo, but without confirmation of both parental samples.' There is no evidence or report of a de novo event for this variant. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 is applied when there is co-segregation with disease in multiple affected family members. The rule states: 'Co-segregation with disease in multiple affected family members.' There is no segregation data provided for this variant. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 is applied for missense variants in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. The rule states: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.' In BRCA1, the spectrum of variants is broad and there is no specific evidence to support PP2 for this variant. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 is applied when multiple computational tools predict a deleterious effect on the gene or its product. The rule states: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product.' In this case, the computational predictions are mixed with some predictors indicating deleterious effects and others (including CADD, PolyPhen, PrimateAI, and REVEL score of 0.37) indicating benign impact; furthermore, SpliceAI predicts no splicing impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 is applied when the patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. The rule states: 'Patient’s phenotype is highly specific for a disease with a single genetic etiology.' There is no detailed phenotypic or family history information provided for this variant. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 is applied when a reputable source has reported the variant as pathogenic without providing the underlying evidence. The rule states: 'Reputable source recently reports variant as pathogenic.' In this instance, ClinVar submissions show conflicting interpretations (ranging from Likely Benign to VUS), and no single reputable assertion is available. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1 is applied when the allele frequency is above 5% in population databases. The rule states: 'Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or ExAC.' The observed MAF (0.00199%) is far below this threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS1 is applied when the allele frequency is greater than expected for the disorder. The rule states: 'Allele frequency is greater than expected for disorder.' In this case, the variant frequency is extremely low. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 is applied when the variant is observed in healthy adult individuals with full penetrance expected at an early age for a dominant disorder. The rule states: 'Observed in a healthy adult individual for a dominant disorder, with full penetrance expected at an early age.' There is no evidence provided regarding such observations for this variant. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to PTEN Pre-processing and standard ACMG guidelines, BS3 is applied when well-established functional studies demonstrate no damaging effect on protein function. The rule states: 'Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.' The evidence notes that the variant has not been functionally characterized, and no such studies confirming lack of damage are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 is applied when there is a lack of segregation with disease in affected family members. The rule states: 'Lack of segregation in affected members of a family.' There is no segregation data available for this variant. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 is applied when missense variants are not a common mechanism of disease for a gene in which only truncating variants cause disease. The rule states: 'Missense variant in a gene for which primarily truncating variants are known to cause disease.' In BRCA1, both missense and truncating variants can be pathogenic; hence, BP1 is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines and VCEP modifications, BP4 is applied when multiple in silico predictions indicate no impact on the gene or its product. The rule states: 'Missense or in-frame variants inside a potentially clinically important functional domain, and no predicted impact via protein change or splicing (with BayesDel no-AF score ≤ 0.15 and SpliceAI ≤ 0.1).' The evidence shows that while some algorithms (MetaSVM, MetaLR) suggest a deleterious effect, others (CADD, PolyPhen, PrimateAI, REVEL score of 0.37) and SpliceAI (no splicing impact) indicate a benign impact. Therefore, BP4 is applied at supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 is applied when the variant is found in a case with a different pathogenic variant that explains the phenotype. The rule states: 'Variant observed in a case with another pathogenic variant in a gene known to cause the disease with no additional phenotype.' There is no such evidence provided for this variant. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 is applied when a variant is reported as benign by a reputable source without available evidence. The rule states: 'Reputable source reports the variant as benign.' Although several clinical laboratories have reported benign or likely benign interpretations in ClinVar, the overall assertion is conflicting (with some labs reporting VUS). Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines and VCEP recommendations, BP7 is applied to silent variants (or intronic variants outside the canonical splice sites) with no predicted splicing impact. The rule states: 'Silent variant with no predicted impact on splicing (SpliceAI ≤ 0.1) or intronic variant outside conserved splice motifs.' Since the variant results in an amino acid change (missense) and is not a silent change, BP7 is not applicable.