17-43082453-A-G

Position:

chr17-43082453-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_007294.4(BRCA1):c.4308T>C(p.Ser1436Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,613,730 control chromosomes in the GnomAD database, including 92,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.30 ( 7439 hom., cov: 32)

Exomes 𝑓: 0.34 ( 85367 hom. )

Consequence

BRCA1
NM_007294.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:29O:2

Conservation

PhyloP100: 0.103

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]

BRCA1 links:

BRCA1 (HGNC:):

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 17-43082453-A-G is Benign according to our data. Variant chr17-43082453-A-G is described in ClinVar as [Benign]. Clinvar id is 125703.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43082453-A-G is described in Lovd as [Likely_benign]. Variant chr17-43082453-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.103 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.4308T>C	p.Ser1436Ser	synonymous_variant	12/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.4308T>C	p.Ser1436Ser	synonymous_variant	12/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.301

AC:

45723

AN:

151996

Hom.:

7437

Cov.:

show subpopulations

Gnomad AFR

AF:

0.181

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.320

Gnomad ASJ

AF:

0.352

Gnomad EAS

AF:

0.369

Gnomad SAS

AF:

0.492

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.332

Gnomad OTH

AF:

0.320

GnomAD3 exomes

AF:

0.349

AC:

87615

AN:

251392

Hom.:

16196

AF XY:

0.358

AC XY:

48594

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.312

Gnomad ASJ exome

AF:

0.363

Gnomad EAS exome

AF:

0.379

Gnomad SAS exome

AF:

0.504

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.325

Gnomad OTH exome

AF:

0.344

GnomAD4 exome

AF:

0.338

AC:

493418

AN:

1461616

Hom.:

85367

Cov.:

AF XY:

0.343

AC XY:

249269

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.175

Gnomad4 AMR exome

AF:

0.315

Gnomad4 ASJ exome

AF:

0.358

Gnomad4 EAS exome

AF:

0.353

Gnomad4 SAS exome

AF:

0.499

Gnomad4 FIN exome

AF:

0.396

Gnomad4 NFE exome

AF:

0.327

Gnomad4 OTH exome

AF:

0.334

GnomAD4 genome

AF:

0.301

AC:

45729

AN:

152114

Hom.:

7439

Cov.:

AF XY:

0.307

AC XY:

22841

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.180

Gnomad4 AMR

AF:

0.320

Gnomad4 ASJ

AF:

0.352

Gnomad4 EAS

AF:

0.369

Gnomad4 SAS

AF:

0.492

Gnomad4 FIN

AF:

0.404

Gnomad4 NFE

AF:

0.332

Gnomad4 OTH

AF:

0.324

Alfa

AF:

0.326

Hom.:

13678

Bravo

AF:

0.284

Asia WGS

AF:

0.406

AC:

1410

AN:

3478

EpiCase

AF:

0.323

EpiControl

AF:

0.333

ClinVar

Significance: Benign

Submissions summary: Benign:29Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:10Other:1

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jan 12, 2015	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.3304 (Asian), 0.128 (African), 0.3588 (European), derived from 1000 genomes (2012-04-30). -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	High frequency in a 1kG or ESP population: 32.6 %. -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 22, 2011	- -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	#N/A -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2015	p.Ser1436Ser in exon 12 of BRCA1: This variant is not expected to have clinical significance because it has been identified in 34.3% of chromosomes from all pop ulations by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs1060915). -

Hereditary breast ovarian cancer syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -

Familial cancer of breast

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -
not provided, no classification provided	literature only	Genomic Research Center, Shahid Beheshti University of Medical Sciences	-	- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.3

DANN

Benign

0.73

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over