rs80357087
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6
The ENST00000357654.9(BRCA1):c.5005G>T(p.Ala1669Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000093 in 1,612,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1669D) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000084 ( 0 hom. )
Consequence
BRCA1
ENST00000357654.9 missense
ENST00000357654.9 missense
Scores
3
9
7
Clinical Significance
Conservation
PhyloP100: 4.72
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 17 uncertain in ENST00000357654.9
BP6
Variant 17-43067677-C-A is Benign according to our data. Variant chr17-43067677-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41831.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2, Likely_benign=10, not_provided=1}. Variant chr17-43067677-C-A is described in Lovd as [Likely_benign]. Variant chr17-43067677-C-A is described in Lovd as [Benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.5005G>T | p.Ala1669Ser | missense_variant | 16/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.5005G>T | p.Ala1669Ser | missense_variant | 16/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes 0.000184 AC: 28AN: 152028Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251344Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135858
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GnomAD4 exome AF: 0.0000835 AC: 122AN: 1460484Hom.: 0 Cov.: 30 AF XY: 0.0000908 AC XY: 66AN XY: 726674
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GnomAD4 genome 0.000184 AC: 28AN: 152028Hom.: 0 Cov.: 30 AF XY: 0.000135 AC XY: 10AN XY: 74256
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:17Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:4
| Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | BRCA1: BS3:Supporting - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 23, 2016 | Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide with 3/4 in silico programs (SNPs&Go effect not captured here due to low reliability index) predict a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 6/121254 (1/20210), which does not exceed the predicted maximum expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in affected individuals via publications including a co-occurrence with another pathogenic BRCA1 variant 2080delA (Judkins_2005) and a lack of co-segregation with disease (Vallon-Christersson_2001). Multiple functional studies showed the variant of interest to act comparable to wild type. In addition, multiple reputable databases/clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. - |
not specified Uncertain:1Benign:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 23, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple reports describe as nonpathogenic; ClinVar: 4 B/LB, 2 VUS - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 11, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 26, 2016 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:2Other:1
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Likely benign, criteria provided, single submitter | literature only | Counsyl | Sep 26, 2014 | - - |
| Likely benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 26, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 09, 2022 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 20, 2016 | - - |
Breast and/or ovarian cancer Benign:2
| Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 24, 2023 | - - |
Breast carcinoma Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 13, 2015 | - - |
Malignant tumor of breast Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Ala1669Ser variant was identified in 1 of 208 proband chromosomes (frequency: 0.005) from individuals or families with breast and ovarian cancer (Stegel 2011).The variant was also identified in dbSNP (ID: rs80357087) “With Uncertain significance allele”, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, LOVD, the ClinVar database (classified as a uncertain significance variant by the BIC, Biesecker Laboratory; classified as likely benign by Ambry Genetics, CSER_CC_NCGL, GeneDX, Counsyl), the BIC database (11X with unknown clinical importance), and UMD (1X as a UV variant).This variant was identified in the Exome Variant Server project in 1 of 8600 European American alleles, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 6 of 77032 chromosomes (6 individuals) from a population of European (Non-Finnish /African individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Ala1669 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Comprehensive analysis study by Lee (2010) identified the variant score no protein folding defect, normal peptide binding activity and specificity, and normal transcriptional activity. The study by Rowling (2010) used biophysical approach to classify the variant and suggested the variant does not have destabilizing effect. Furthermore, conservation analysis by Abkevich (2004) classified the variant as likely to be neutral or of little clinical significance. In addition, this variant was identified in trans with known deleterious mutations (2080delA) (Judkins 2005), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. - |
Familial cancer of breast Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: PM1,PP3,BP6,BS1. - |
Hereditary breast ovarian cancer syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;T;.;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;N;.;N;N;N;N;N
REVEL
Pathogenic
Sift
Benign
T;D;.;T;.;D;T;D;T;T
Sift4G
Benign
T;D;D;T;D;D;T;.;.;D
Polyphen
0.64, 1.0
.;P;.;.;.;.;.;.;D;.
Vest4
MVP
MPC
0.13
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at