17-43091792-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_007294.4(BRCA1):​c.3739G>A​(p.Val1247Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,168 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 1 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

2
17

Clinical Significance

Benign reviewed by expert panel U:2B:15

Conservation

PhyloP100: -0.675
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 Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.017272323).
BP6
Variant 17-43091792-C-T is Benign according to our data. Variant chr17-43091792-C-T is described in ClinVar as [Benign]. Clinvar id is 54985.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091792-C-T is described in Lovd as [Benign]. Variant chr17-43091792-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.3739G>A p.Val1247Ile 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.3739G>A p.Val1247Ile missense_variant 10/231 NM_007294.4 ENSP00000350283 P4P38398-1

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00135
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000955
AC:
24
AN:
251266
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135792
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000356
AC:
52
AN:
1461862
Hom.:
1
Cov.:
32
AF XY:
0.0000234
AC XY:
17
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000529
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.0000806
AC XY:
6
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00135
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000761
Hom.:
0
Bravo
AF:
0.0000869
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000906
AC:
11
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Uncertain:2Benign:15
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:5
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoAug 29, 2022- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 26, 2019Variant summary: BRCA1 c.3739G>A (p.Val1247Ile) 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 9.5e-05 in 282924 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.001 in the gnomAD database. This frequency is about the same that is expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.001), suggesting that the variant might be a benign polymorphism found primarily in populations of East Asian origin. c.3739G>A has been reported in the literature in individuals, mostly of East Asian origin, affected with breast or ovarian cancer, however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5213_5216delCTTA (p.Thr1738fsX2) in the UMD BRCA1 database), providing supporting evidence for a benign role. In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, predicted this variant to be likely neutral (Easton 2007 and Lindor 2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (3x) while the expert panel ruled on its classification as benign (1x). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:3
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)May 29, 2002- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Aug 10, 2015IARC 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 = 0.00000251 -
Benign, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Feb 03, 2010- -
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 02, 2022- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 18, 2014This alteration is classified as 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 submittercurationSema4, Sema4Feb 03, 2021- -
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 23, 2020This variant is associated with the following publications: (PMID: 27153395, 24916970, 25682074, 17924331, 15385441, 18824701, 15235020, 25337278, 26689913, 16826315, 27157322, 22753008, 18779604, 21990134, 27907908, 16267036, 10923033, 23704879, 33087888) -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-- -
Familial cancer of breast Benign:1
Likely benign, no assertion criteria providedliterature onlyCenter for Precision Medicine, Meizhou People's Hospital-- -
BRCA1-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 26, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
0.35
DANN
Benign
0.67
DEOGEN2
Benign
0.085
T;.;.;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.052
N
LIST_S2
Benign
0.55
T;T;T;T
M_CAP
Uncertain
0.26
D
MetaRNN
Benign
0.017
T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.4
L;L;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.050
N;N;N;N
REVEL
Uncertain
0.42
Sift
Benign
0.37
T;T;T;T
Sift4G
Benign
0.45
T;T;T;T
Polyphen
0.15
B;.;.;B
Vest4
0.27
MVP
0.19
MPC
0.071
ClinPred
0.0096
T
GERP RS
-2.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.017
gMVP
0.066

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: rs80357191; hg19: chr17-41243809; COSMIC: COSV58789777; COSMIC: COSV58789777; API