BRCA2 c.171C>T, p.Tyr57=
NM_000059.4:c.171C>T
COSMIC ID: COSM9497052
Likely Benign
This synonymous BRCA2 variant shows no impact on splicing or protein function, is extremely rare in population databases, and is supported by reputable benign assertions. Application of one strong and multiple supporting benign criteria leads to a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP1
BP4
BP6
BP7
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.171C>T
Protein Change
Y57=
Location
Exon 3
(Exon 3 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM9497052
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.171C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000796%
Very Rare
Highest in Population
East Asian
0.00544%
Rare
Global: 0.000796%
East Asian: 0.00544%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251356Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000796%, 2/251356 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.00544%, 1/18394 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
4 publications
Likely Benign
Based on 7 submitter reviews in ClinVar
Submitter Breakdown
7 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
This submission and the accompanying classification are no longer maintained by the submitter.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 Likely benign (7 clinical laboratories) and as Likely Benign (1 clinical laboratories) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel.
Expert Panel Reviews
Likely 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.07
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 it is a synonymous (Y57=) change with no disruption of the coding sequence. Therefore, this criterion is not applied because the variant is not a null variant.
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..." The evidence for this variant shows no amino acid change (synonymous). Therefore, this criterion is not applied because the variant does not alter the protein sequence.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There is no de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 is: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect..." There are no functional studies for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to controls..." There are no case-control data showing enrichment in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 is: "Moderate Apply if variant is in a mutational hotspot or well-established functional domain without benign variation..." The variant is outside the defined BRCA2 functional domains (aa 10–40 and 2481–3186). Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 Supporting is: "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 a MAF of 0.000796% in gnomAD (2/251 356 alleles), meeting the rarity threshold. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 is: "Apply for BRCA-related Fanconi Anemia cases with co-occurring variants..." There is no Fanconi Anemia or trans configuration evidence. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 is: "Protein length changes due to in-frame indels or stop-loss variants..." The variant is synonymous with no change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 is: "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen..." The variant is synonymous, not a PTC. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 is: "Assumed de novo, without confirmation of paternity and maternity..." There is no de novo evidence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 is: "Co-segregation with disease in multiple 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 is: "Missense variant in a gene with low rate of benign missense variation..." The variant is synonymous, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 is: "Supporting Apply PP3 for missense or in-frame variants inside a functional domain predicted damaging..." The variant is synonymous and computational tools predict no impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 is: "Use to capture combined LR based on multifactorial likelihood clinical data..." No phenotype-driven likelihood data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 is: "Reputable source reports variant as pathogenic..." Only benign assertions exist. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 is: "Stand Alone Filter allele frequency (FAF) > 0.1% in gnomAD..." The variant MAF (0.000796%) is well below 0.1%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 is: "Strong Filter allele frequency (FAF) > 0.01% and ≤0.1%..." The variant MAF (0.000796%) is below 0.01%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 is: "Applied in absence of features of recessive disease (Fanconi Anemia)..." No data on healthy individuals without FA phenotype. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 is: "Strong Well-established functional studies show no damaging effect..." No functional studies exist. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 is: "Strong Lack of segregation in affected family members..." No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, BP1_Strong is: "Apply BP1_Strong for silent substitution, missense or in-frame variants outside a functional domain AND no splicing predicted (SpliceAI ≤0.1)." The variant is a silent change at codon 57 (outside domains aa 10–40 and 2481–3186) with SpliceAI=0. Therefore, this criterion is applied at Strong strength because it meets domain and splicing criteria.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene..." No trans observations with pathogenic variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 is: "In-frame indels in repetitive regions without known function..." The variant is not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (e.g., conservation, splicing algorithms)." SpliceAI predicts no splicing impact (score=0) and CADD is benign. Therefore, this criterion is applied at Supporting strength because computational tools uniformly predict no effect.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 is: "Use to capture combined LR against pathogenicity based on multifactorial data..." No multifactorial data or co-observation scenarios. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available for independent evaluation." ClinVar and ENIGMA report this variant as Likely Benign. Therefore, this criterion is applied at Supporting strength because multiple reputable sources assert benign status without underlying data.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, BP7 is: "Synonymous variant for which splicing prediction algorithms predict no impact on splicing and the nucleotide is not highly conserved." SpliceAI predicts no splicing impact (score=0). Therefore, this criterion is applied at Supporting strength because it is a synonymous change with no predicted splicing effect.