BRCA1 c.2428A>T, p.Asn810Tyr
NM_007294.4:c.2428A>T
COSMIC ID: COSM7343749, COSM7343750
Variant of Uncertain Significance (VUS)
Functional assays demonstrating no damaging effect (BS3_Strong), low-level population frequency consistent with benign (BS1_Supporting), and location outside key functional domains with no splicing impact (BP1_Strong) combine to classify p.N810Y as Benign.
ACMG/AMP Criteria Applied
BS1
BS3
BP1
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.2428A>T
Protein Change
N810Y
Location
Exon 10
(Exon 10 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 810 in gene BRCA1
Alternate Identifiers
COSM7343749, COSM7343750
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.2428A>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00638%
Rare
Highest in Population
Remaining individuals
0.0139%
Low Frequency
Global: 0.00638%
Remaining individuals: 0.0139%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 281928Alt: 18Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00638%, 18/281928 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0139%, 1/7192 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
3 publications
Uncertain Significance (VUS)
Based on 14 submitter reviews in ClinVar
Submitter Breakdown
1 VUS
4 LB
9 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 = 0.000000000000233
This submission and the accompanying classification are no longer maintained by the submitter.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 (9 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Uncertain significance (1 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 810 in gene BRCA1
Functional Summary
The BRCA1 N810Y variant has been functionally characterized and is likely neutral. In vitro studies using a cisplatin sensitivity assay indicate that this mutation does not significantly alter the function of the BRCA1 protein compared to the wildtype.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.462
0.462
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:
polyphen_prediction: probably_damagingmetalr: D
Benign:
CADD: 2.81metasvm: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, "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." is the rule for PVS1. The evidence for this variant shows a missense substitution (p.N810Y), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, "Apply PS1 for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI ≤0.1))." The evidence for this variant shows no previously established pathogenic variant at amino acid position 810. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history" is the rule for PS2. No evidence of de novo occurrence is provided for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect" is the rule for PS3. The functional evidence shows no damaging effect in cisplatin sensitivity assays compared to wildtype. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, "Strong The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls" is the rule for PS4. No case-control or affected individual data are available for p.N810Y. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants located within a defined clinically important functional domain. The evidence shows p.N810Y is outside the RING (aa 2–101), coiled-coil (aa 1391–1424), and BRCT (aa 1650–1857) domains. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, "Supporting Absent from controls in an outbred population, from gnomAD v2.1 and v3.1" is the rule for PM2. The evidence shows the variant is present in gnomAD non-cancer exomes at MAF=0.00638%. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to recessive co-occurrence in Fanconi anemia phenotypes. No such co-occurrence data are available for this variant. 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 evidence shows p.N810Y is a missense substitution, not a length-altering variant. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies when a different proven pathogenic missense change at the same residue has been observed. There is no evidence of a known pathogenic variant at residue N810. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo occurrences without confirmation. No such data are available for this variant. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies to co-segregation with disease in multiple affected family members. No segregation data are provided for p.N810Y. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, "Missense variant in a gene with a low rate of benign missense variation and where missense is a common mechanism" is the rule for PP2. BRCA1 has a mix of benign and pathogenic missense variants, and no evidence supports a low benign missense rate here. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies to missense or in-frame variants inside a functional domain with predicted impact (BayesDel no-AF ≥0.28) or predicted splicing impact (SpliceAI ≥0.2). The evidence shows p.N810Y is outside all defined domains and SpliceAI=0. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies to multifactorial likelihood clinical data for breast cancer phenotype. No such data are available for p.N810Y. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 (reputable source declarations without evidence) is deprecated and should not be applied. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, "Stand Alone Filter allele frequency (FAF) is above 0.1%" is the rule for BA1. The evidence shows MAF=0.00638%, below this threshold. Therefore, this criterion is not applied.
BS1
BS1 (Supporting) Strength Modified
According to VCEP guidelines, "Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001)" is the rule for BS1 Supporting. The evidence shows MAF=0.00638% in gnomAD non-cancer exomes, which falls within this range. Therefore, this criterion is applied at Supporting strength.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies to observations in healthy adults without a recessive phenotype. No such healthy adult data are available for this variant. Therefore, this criterion is not applied.
BS3
BS3 (Strong)
According to VCEP guidelines, "Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function" is the rule for BS3. The evidence shows that cisplatin sensitivity assays indicate p.N810Y does not significantly alter BRCA1 function. Therefore, this criterion is applied at Strong strength.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies to lack of segregation in affected family members. No segregation analysis is provided. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, "Strong Apply BP1_Strong for silent substitution, missense or in-frame variants outside a clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)" is the rule for BP1. The evidence shows p.N810Y is outside the RING, coiled-coil, and BRCT domains and SpliceAI=0. Therefore, this criterion is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to observation in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant. No such co-observation data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, BP3 applies to in-frame indels in repetitive regions without functional impact. p.N810Y is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 applies to missense variants inside clinically important domains with benign computational predictions. p.N810Y is outside those domains and has mixed in silico results. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies to variants observed in a case with an alternate molecular basis for disease. No such data are available for this variant. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 (reputable source reports without evidence) is deprecated and should not be applied. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants without splicing impact. p.N810Y is a missense substitution. Therefore, this criterion is not applied.