chr17-43091990-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBP6_Very_Strong

The NM_007294.4(BRCA1):​c.3541G>A​(p.Val1181Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,614,060 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. V1181V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

2
17

Clinical Significance

Benign reviewed by expert panel U:3B:12

Conservation

PhyloP100: 0.277
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 -10 ACMG points.

PM1
In a compositionally_biased_region Polar residues (size 15) in uniprot entity BRCA1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_007294.4
BP4
Computational evidence support a benign effect (MetaRNN=0.02566573).
BP6
Variant 17-43091990-C-T is Benign according to our data. Variant chr17-43091990-C-T is described in ClinVar as [Benign]. Clinvar id is 54911.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.3541G>A p.Val1181Ile 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.3541G>A p.Val1181Ile missense_variant 10/231 NM_007294.4 ENSP00000350283 P4P38398-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000756
AC:
19
AN:
251184
Hom.:
1
AF XY:
0.000110
AC XY:
15
AN XY:
135800
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000457
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000472
AC:
69
AN:
1461798
Hom.:
1
Cov.:
39
AF XY:
0.0000619
AC XY:
45
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000290
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000324
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152262
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.0000481
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000387
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000906
AC:
11
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Benign
Submissions summary: Uncertain:3Benign:12
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoApr 24, 2019- -
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 29, 2018This variant is denoted BRCA1 c.3541G>A at the cDNA level, p.Val1181Ile (V1181I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant, also known as 3660G>A using alternate nomenclature, was observed in at least one individual with a family history of breast and/or ovarian cancer (Konecny 2011). BRCA1 Val1181Ile was observed at an allele frequency of 0.05% (14/30,778) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Val1181Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesDec 16, 2020- -
not specified Uncertain:1Benign:2
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 21, 2021Variant summary: BRCA1 c.3541G>A (p.Val1181Ile) 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. This variant has also been predicted to be neutral by studies based on sequence alignment, chemical difference measurement, and conservation analysis (Abkevich_2004, Pavlicek_2004). A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign (CAGI class 1) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). The variant allele was found at a frequency of 8e-05 in 273756 control chromosomes, predominantly at a frequency of 0.00046 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (8e-05 vs 0.001), allowing no conclusion about variant significance. c.3541G>A, has been reported in the literature in individuals affected with Breast and Ovarian Cancer and in unaffected controls without strong evidence for causality (example, Konecny_2011, Judkins_2005, Yilmaz_2016, Zhang_2015, Momozawa_2018, Fujita_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 but one submitter has rendered a classification as benign (n=1, expert panel)/likely benign (n=4). Based on the lack of any evidence supporting an actionable outcome in a cross-sectional review of literature spanning at-least 16 years of evolution, and the predominant consensus among peers supporting a neutral outcome as outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJan 08, 2021DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.3541G>A, in exon 10 that results in an amino acid change, p.Val1181Ile. This sequence change has been described in the gnomAD database with a frequency of 0.046% in the South Asian sub-population (dbSNP rs56336919). The p.Val1181Ile change has been reported in one case-control study; however, its presence in cases versus controls was not specified (PMID: 30287823). Additionally, a different amino acid change at the same location, p.Val1181Ala, has been reported in association with breast and/or ovarian cancer (PMID: 30702160). The p.Val1181Ile change affects a moderately conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Val1181Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val1181Ile change remains unknown at this time. -
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:2
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 = 0.000066 -
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthNov 20, 2023- -
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)May 29, 2002- -
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 18, 2019This 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 11, 2016- -
Likely benign, criteria provided, single submittercurationSema4, Sema4Nov 23, 2021- -
BRCA1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 27, 2023This variant is classified as likely 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
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
3.2
DANN
Benign
0.70
DEOGEN2
Benign
0.17
T;.;.;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.062
N
LIST_S2
Benign
0.78
T;T;T;T
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.026
T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Uncertain
2.1
M;M;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.55
N;N;N;N
REVEL
Uncertain
0.38
Sift
Benign
0.26
T;T;T;T
Sift4G
Benign
0.23
T;T;T;T
Polyphen
0.0070
B;.;.;B
Vest4
0.25
MVP
0.18
MPC
0.084
ClinPred
0.0058
T
GERP RS
-1.8
Varity_R
0.020
gMVP
0.030

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: rs56336919; hg19: chr17-41244007; COSMIC: COSV105897766; COSMIC: COSV105897766; API