rs80357002

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_007294.4(BRCA1):​c.4765C>T​(p.Arg1589Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R1589P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

1
6
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:9

Conservation

PhyloP100: 0.345
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.23940855).
BP6
Variant 17-43071149-G-A is Benign according to our data. Variant chr17-43071149-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55283.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=3}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.4765C>T p.Arg1589Cys missense_variant 15/23 ENST00000357654.9 NP_009225.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.4765C>T p.Arg1589Cys missense_variant 15/231 NM_007294.4 ENSP00000350283 P4P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251386
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135858
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461884
Hom.:
0
Cov.:
33
AF XY:
0.00000963
AC XY:
7
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 28, 2020DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.4765C>T, in exon 15 that results in an amino acid change, p.Arg1589Cys. This sequence change has been described in the gnomAD database in three individuals (dbSNP rs80357002). The p.Arg1589Cys change has been described in one individual from a hereditary breast and ovarian cancer family (PMID: 16267036). The p.Arg1589Cys change affects a poorly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1589Cys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1589Cys change remains unknown at this time. -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 06, 2024Variant summary: BRCA1 c.4765C>T (p.Arg1589Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251386 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant has been reported in HBOC families, however with limited information (i.e. no data about co-occurrence and cosegregation provided) (example, Judkins_2005, Lincoln_2015, Kim_2020). However, a reputable database (BIC) cites the variant to co-occur with a pathogenic BRCA2 variant (c.1929delG), suggesting that it was not a primary cause of disease in the patient. A large case-control study evaluating breast cancer genetic risk also reported this variant was absent in the case cohorts (Dorling_2021, 1/53461 controls). In addition, this variant had similar transcription activation activity in comparison to wildtype (Woods_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 16267036, 31907386, 26207792, 15385441, 28781887). ClinVar contains an entry for this variant (Variation ID: 55283). Based on the evidence outlined above, the variant was classified as uncertain significance-possibly benign. -
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 19, 2016This 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 submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalJul 31, 2024- -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:2
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)Feb 20, 2004- -
Uncertain significance, criteria provided, single submitterclinical testingMolecular Endocrinology Laboratory, Christian Medical College-- -
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthOct 23, 2023- -
Benign, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Aug 10, 2012- -
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 21, 2016- -
Likely benign, criteria provided, single submittercurationSema4, Sema4Mar 28, 2021- -
Likely benign, no assertion criteria providedclinical testingTrue Health DiagnosticsMay 30, 2018- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 26, 2018This 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. -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
0.030
CADD
Benign
13
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
.;T;.;.;T;.;.;.;T;.
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.79
FATHMM_MKL
Benign
0.049
N
LIST_S2
Benign
0.85
D;D;D;T;D;D;D;D;D;D
M_CAP
Pathogenic
0.48
D
MetaRNN
Benign
0.24
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
0.0
.;N;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.7
N;N;.;N;.;N;N;N;N;N
REVEL
Uncertain
0.53
Sift
Uncertain
0.0080
D;D;.;D;.;D;D;D;D;D
Sift4G
Uncertain
0.018
D;D;D;D;T;D;D;.;.;D
Polyphen
0.096, 0.27
.;B;.;.;.;.;.;.;B;.
Vest4
0.18
MVP
0.63
MPC
0.20
ClinPred
0.18
T
GERP RS
2.5
Varity_R
0.061
gMVP
0.17

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80357002; hg19: chr17-41223166; COSMIC: COSV58792764; COSMIC: COSV58792764; API