chr17-43092934-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PP3_ModerateBP6_Very_Strong

The NM_007294.4(BRCA1):​c.2597G>A​(p.Arg866His) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R866C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

7
9
3

Clinical Significance

Benign reviewed by expert panel P:1U:12B:4

Conservation

PhyloP100: 4.92
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 -6 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.885
BP6
Variant 17-43092934-C-T is Benign according to our data. Variant chr17-43092934-C-T is described in ClinVar as [Benign]. Clinvar id is 54613.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092934-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.2597G>A p.Arg866His missense_variant 10/23 ENST00000357654.9 NP_009225.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.2597G>A p.Arg866His missense_variant 10/231 NM_007294.4 ENSP00000350283 P4P38398-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251054
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135704
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1461432
Hom.:
0
Cov.:
42
AF XY:
0.0000151
AC XY:
11
AN XY:
727008
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:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000243
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Benign
Submissions summary: Pathogenic:1Uncertain:12Benign:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:4Benign:1
Benign, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Jun 18, 2019IARC 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 = 0.000574 -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 01, 2023This missense variant replaces arginine with histidine at codon 866 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with breast cancer (PMID: 18273839, 25948282, 32846166, 34218100), an individual affected with ovarian cancer (PMID: 24504028) and in a breast cancer case-control meta-analysis in 4/60466 cases and 5/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001643). A multifactorial analysis has reported likelihood ratios for pathogenicity of 1.1768 and 0.0239 based on co-occurrence and family history, respectively (PMID: 31131967). This variant has been identified in 5/282454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)May 28, 2009- -
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)Dec 23, 2003- -
Uncertain significance, criteria provided, single submitterclinical testingMichigan Medical Genetics Laboratories, University of MichiganNov 03, 2014- -
Hereditary breast ovarian cancer syndrome Pathogenic:1Benign:2
Benign, criteria provided, single submitterclinical testingMendelicsAug 22, 2023- -
Likely pathogenic, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateNov 16, 2021- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 26, 2023Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Anczukow et al., 2008; Cunningham et al., 2014; Kluska et al., 2015; Van der Merwe et al., 2022; Guindalini et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2716G>A; This variant is associated with the following publications: (PMID: 25948282, 15385441, 23893897, 25348012, 20104584, 12938098, 25528188, 18273839, 24504028, 28993434, 32846166, 34218100, 35464868, 33087888, 31131967, 15343273, 35264596) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMar 26, 2019- -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The BRCA1 p.Arg866His variant was identified in 3 of 8500 proband chromosomes (frequency: 0.0004) from American, Polish, German and Malaysian individuals or families with breast or ovarian cancer and was present in 1 of 5618 control chromosomes (frequency:0.0002) from healthy individuals (Cunningham 2014, Kluska 2015, Meyer 2003, Wen 2018). In a functional study using a minigene assay to look at the splicing effect of BRCA1 exon 11 unclassified variants, the variant did not show an effect on splicing (Anczuków 2008). The variant was identified in dbSNP (ID: rs80356911) “With Uncertain significance allele”, ClinVar (classified as uncertain significance; submitters: Ambry Genetics, GeneDx, Invitae, SCRP, BIC, Michigan Medical Genetics Laboratories (University of Michigan), Integrated Genetics Laboratory Corporation of America, Mendelics and Quest Diagnostics Nichols Institute San Juan Capistrano), LOVD 3.0, and UMD-LSDB (classified 3-UV). The variant was identified in control databases in 5 of 276800 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 1 of 24024 chromosomes (freq: 0.00004), European Non-Finnish in 3 of 126552 chromosomes (freq: 0.00002), and South Asian in 1 of 30766 chromosomes (freq: 0.00003) while not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Arg866 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 30, 2023This missense variant replaces arginine with histidine at codon 866 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with breast cancer (PMID: 18273839, 25948282, 32846166, 34218100), an individual affected with ovarian cancer (PMID: 24504028) and in a breast cancer case-control meta-analysis in 4/60466 cases and 5/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001643). A multifactorial analysis has reported likelihood ratios for pathogenicity of 1.1768 and 0.0239 based on co-occurrence and family history, respectively (PMID: 31131967). This variant has been identified in 5/282454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 04, 2023The p.R866H variant (also known as c.2597G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2597. The arginine at codon 866 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Cunningham JM et al. Sci Rep, 2014 Feb;4:4026; Kluska A et al. BMC Med Genomics, 2015 May;8:19; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190; Van der Merwe NC et al. Front Genet, 2022 Apr;13:834265). However, it has been detected in 0/2575 unselected patients with breast cancer and in 1/2809 healthy control individuals from a Malaysian cohort (Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103). This variant was tested in a minigene assay and showed normal splicing (Anczuków O et al. Genes Chromosomes Cancer, 2008 May;47:418-26). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Sep 20, 2021- -
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 11, 2023Variant summary: BRCA1 c.2597G>A (p.Arg866His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251054 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2597G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer without strong evidence for causality (e.g. Meyer_2003, Anczukow_2008, Cunningham_2014, Kluska_2015, Yildiz Tacar_2020, Combrink_2021, Guindalini_2022, Van der Merwe_2022) and also in a healthy control individual in a cohort of Asian individuals with and without breast cancer (Wen_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A study performing a multifactorial likelihood analysis based on collected research and clinical data has classified the variant as benign (Parsons_2019). Additionally, one clinical lab reported the variant in an ovarian cancer patient who also carried a co-occurring pathogenic BRCA2 variant, providing support for a benign role (Invitae via ClinVar). The following publications have been ascertained in the context of this evaluation (PMID: 18273839, 34218100, 24504028, 35264596, 25948282, 12938098, 31112341, 15385441, 35464868, 28993434, 32846166). Nine submitters, including the expert panel ENIGMA, have cited clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as uncertain significance, three submitters (including the expert panel) classified it as benign/likely benign and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalFeb 06, 2024- -
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioDec 20, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.66
D;.;.;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.88
D;D;D;D
MetaSVM
Uncertain
0.71
D
MutationAssessor
Pathogenic
3.1
M;M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.7
D;D;D;D
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0080
D;D;D;D
Sift4G
Uncertain
0.0070
D;D;D;D
Polyphen
1.0
D;.;.;D
Vest4
0.82
MutPred
0.71
Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);.;Loss of MoRF binding (P = 0.0152);
MVP
0.91
MPC
0.47
ClinPred
0.88
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.25
gMVP
0.43

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: rs80356911; hg19: chr17-41244951; API