BRCA2 c.4850G>A, p.Ser1617Asn
NM_000059.4:c.4850G>A
Variant of Uncertain Significance (VUS)
p.Ser1617Asn is a missense variant outside defined functional domains with no compelling pathogenic evidence and only one strong benign criterion (BP1). Insufficient evidence for benign or pathogenic classification, remaining a Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
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.4850G>A
Protein Change
S1617N
Location
Exon 11
(Exon 11 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 1617: S1617G, S1617R, S1617I
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.4850G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0012%
Rare
Highest in Population
European (non-Finnish)
0.00265%
Rare
Global: 0.0012%
European (non-Finnish): 0.00265%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 249944Alt: 3Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0012%, 3/249944 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00265%, 3/113110 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
4 publications
Uncertain Significance (VUS)
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
3 VUS
5 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
In the published literature, this variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), 21120943 (2011), 21232165 (2011)). Additionally, the variant has been reported in healthy, unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). The frequency of this variant in the general population, 0.000027 (3/113110 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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).
Variant summary: BRCA2 c.4850G>A (p.Ser1617Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 356946 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4850G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Stegel_2011, Dorling_2021) but it was also reported in unaffected controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA2 c.3599_3600delGT, p.Cys1200X; UMD), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and three ClinVar submitters (evaluation after 2014) cite it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Uncertain significance (3 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 1617: S1617G, S1617R, S1617I
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.193
0.193
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
Benign:
CADD: 0.32polyphen_prediction: benignmetasvm: Tmetalr: 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, 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 is a known mechanism of disease." The evidence for this variant shows: NM_000059.4:c.4850G>A (p.Ser1617Asn) 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 – same predicted protein change as a previously established pathogenic variant (no confirmed or predicted splicing effect)." The evidence for this variant shows: there is no previously established pathogenic variant causing the same p.Ser1617Asn 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 information on de novo occurrence is 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 studies have been performed for p.Ser1617Asn. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong – prevalence in affected individuals is significantly increased compared to controls (case-control studies with p≤0.05 and OR≥4)." The evidence for this variant shows: no case-control or case prevalence data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate – missense variant in a known functional domain (BRCA2 PALB2 binding aa 10-40 or DNA binding aa 2481-3186)." The evidence for this variant shows: p.Ser1617Asn lies outside these defined domains. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2_Supporting is: "Absent from controls in gnomAD v2.1 (non-cancer) and gnomAD v3.1." The evidence for this variant shows: present at MAF=0.0012% in gnomAD non-cancer. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Supporting – observed in trans with a pathogenic variant in a patient with a consistent Fanconi Anemia phenotype." The evidence for this variant shows: no Fanconi Anemia phenotype or trans observations. 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 (in-frame indels or stop-loss)." The evidence for this variant shows: it is a missense change, not a length-altering variant. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5_PTC is: "Supporting/Moderate/Strong – protein termination codon variant at an exon with another proven pathogenic PTC." The evidence for this variant shows: it is a missense change and no different pathogenic missense at p.1617 has been reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Unconfirmed de novo occurrence without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1_Strong is: "Co-segregation with disease in multiple affected family members (Bayes LR≥18.7)." The evidence for this variant shows: no segregation data are available. 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 variants and where missense is a common disease mechanism." The evidence for this variant shows: BRCA2 has both loss-of-function and missense pathogenic variants. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting – missense variant inside a functional domain with predicted impact (BayesDel≥0.30 or SpliceAI≥0.2)." The evidence for this variant shows: it lies outside defined domains and computational scores (REVEL=0.19, SpliceAI≤0.1) do not predict impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting/Moderate/Strong – multifactorial likelihood clinical data for breast/ovarian cancer risk." The evidence for this variant shows: no 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 published evidence." The evidence for this variant shows: ClinVar submissions are conflicting (Likely benign and VUS). 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) >0.1% in gnomAD non-cancer populations." The evidence for this variant shows: MAF=0.0012% (<0.1%). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong – FAF >0.01% in gnomAD non-cancer." The evidence for this variant shows: MAF=0.0012% (<0.01%). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong – observed in healthy adults without recessive phenotype (Fanconi Anemia) points-based." The evidence for this variant shows: no healthy adult phenotype 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 studies available. 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 LR≤0.05)." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, the rule for BP1_Strong is: "Silent substitution, missense or in-frame variants outside a functional domain (aa 10-40 or 2481-3186) AND no splicing predicted (SpliceAI≤0.1)." The evidence for this variant shows: p.Ser1617Asn is outside defined domains and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting – observed in trans with a pathogenic variant in multigene context without specific phenotype." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP3 is: "Supporting – in-frame indels in repetitive region without known function." The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting – missense/in-frame inside functional domain AND no predicted impact (BayesDel≤0.18 and SpliceAI≤0.1)." The evidence for this variant shows: it is outside defined domains; computational scores are benign but outside domain. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting – co-occurrence with pathogenic variants in other known risk genes without specific phenotype." The evidence for this variant shows: no co-occurrence data. 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: conflicting ClinVar assertions. 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 variants outside conserved splice sites with no predicted impact." The evidence for this variant shows: it is missense. Therefore, this criterion is not applied.