BRCA2 c.4570T>G, p.Phe1524Val
NM_000059.4:c.4570T>G
COSMIC ID: COSM4666042
Variant of Uncertain Significance (VUS)
BRCA2 F1524V is an extremely rare missense variant outside known functional domains with no evidence of deleterious effect from computational or functional studies. It meets one Supporting benign criterion (PM2) and one Strong benign criterion (BP1), resulting in a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP1
Genetic Information
Gene & Transcript Details
Gene
BRCA2
Transcript
NM_000059.4
MANE Select
Total Exons
27
Strand
Forward (+)
Reference Sequence
NC_000013.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000059.2 | Alternative | 27 exons | Forward |
| NM_000059.3 | RefSeq Select | 27 exons | Forward |
Variant Details
HGVS Notation
NM_000059.4:c.4570T>G
Protein Change
F1524V
Location
Exon 11
(Exon 11 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1524 in gene BRCA2
Alternate Identifiers
COSM4666042
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.4570T>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00248%
Rare
Highest in Population
European (non-Finnish)
0.00544%
Rare
Global: 0.00248%
European (non-Finnish): 0.00544%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 281936Alt: 7Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00248%, 7/281936 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00544%, 7/128590 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
3 publications
Uncertain Significance (VUS)
Based on 17 submitter reviews in ClinVar
Submitter Breakdown
2 VUS
3 LB
12 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000208
Variant summary: BRCA2 c.4570T>G (p.Phe1524Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250548 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4570T>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Caux-Moncoutier 2009, Haffty 2009, Meyer 2003, Meyer 2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A review of a multifactorial probability based model (Lindor 2012) that included a statistical weighting of segregation analysis, co-occurrence in trans, pathological profiles, personal and family history of cancer showed that, for this variant, odds in favor of causality was 1.02x10-3 and posterior probability of being deleterious was 2.08x10-5. Authors classify the variant as IARC Class 1 (Least Likely to be pathogenic) variant. Five ClinVar submissions including an expert panel (evaluation after 2014) cite the variant twice as benign and three times as likely benign. Based on the evidence outlined above, the variant was classified as benign.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Clinical Statement
This variant has been reported in ClinVar as Benign (12 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel.
Expert Panel Reviews
Benign
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
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 1524 in gene BRCA2
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, 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 (LOF) is a known mechanism of disease." The evidence for this variant shows: NM_000059.4:c.4570T>G (F1524V) is a missense change, 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. Predicted missense substitutions where a previously classified pathogenic variant results in the same amino acid change (no confirmed or predicted effect on mRNA splicing)." The evidence for this variant shows: no previously established pathogenic variant produces the F1524V amino acid change. 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: no de novo data available. 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 characterization of BRCA2 F1524V is available. 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 controls (p≤0.05, OR≥4)." The evidence for this variant shows: no case-control or prevalence data available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate. Located in a mutational hotspot or well‐studied functional domain without benign variation." The evidence for this variant shows: F1524 lies outside the BRCA2 PALB2 binding domain (aa 10–40) and DNA binding domain (aa 2481–3186). 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 in gnomAD v2.1 and v3.1." The evidence for this variant shows: MAF = 0.00248% in gnomAD (7/281936 alleles), extremely rare. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Supporting to Strong. Observed in trans with a pathogenic variant in patients with Fanconi Anemia phenotype; points-based system." The evidence for this variant shows: no co-occurrence data in FA patients. 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 as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: F1524V is a missense change with no length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate. A novel missense change at an amino acid residue where a different pathogenic missense change has been seen." The evidence for this variant shows: no other pathogenic variant reported at residue F1524. 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/maternity." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting to Strong. Co-segregation with disease in multiple affected family members (Bayes Score–based)." The evidence for this variant shows: no segregation data. 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 variants are a common mechanism of disease." The evidence for this variant shows: BRCA2 has both benign and pathogenic missense variants; this residue is not established as mutation-intolerant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting. In silico predictions of deleterious effect (BayesDel ≥0.30 or SpliceAI ≥0.2) in a functional domain." The evidence for this variant shows: SpliceAI = 0.01 and BayesDel no-AF score not ≥0.30. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting. Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (LR≥2.08)." The evidence for this variant shows: no specific phenotype or multifactorial 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 without available evidence." The evidence for this variant shows: ClinVar entries conflicting (Benign, Likely benign, VUS), no unanimous pathogenic report. 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 (FAF) >0.001 in gnomAD non-cancer populations." The evidence for this variant shows: FAF = 0.0000248 (<0.001). 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 (FAF) >0.0001 and ≤0.001 in gnomAD non-cancer populations." The evidence for this variant shows: FAF = 0.0000248 (<0.0001). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Supporting to Strong. Observed in healthy adults without Fanconi Anemia features (points-based)." The evidence for this variant shows: no healthy adult evaluation data. 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 assays demonstrating benign 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 (Bayes Score ≤0.05)." The evidence for this variant shows: no segregation analysis. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, the rule for BP1_Strong is: "Strong. Silent substitution or missense variant outside a clinically important functional domain and no predicted splice impact (SpliceAI ≤0.1)." The evidence for this variant shows: F1524V is a missense change outside the PALB2 (aa 10–40) and DNA binding (aa 2481–3186) domains, SpliceAI = 0.01. Therefore, this criterion is applied at Strong strength.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting. Missense or in-frame variants inside a functional domain with no predicted impact (BayesDel ≤0.18, SpliceAI ≤0.1)." The evidence for this variant shows: F1524V lies outside defined functional domains. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting. Variant found in a case with an alternate molecular basis for the disease." The evidence for this variant shows: no co-occurrence with other pathogenic variants. 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 evidence." The evidence for this variant shows: ClinVar includes conflicting benign and VUS assertions; no single reputable consensus. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting. Silent or intronic variant outside splice sites with no predicted splice impact (SpliceAI ≤0.1)." The evidence for this variant shows: F1524V is a missense change, not silent or intronic. Therefore, this criterion is not applied.