rs1800744

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000357654.9(BRCA1):c.4535G>T(p.Ser1512Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,614,128 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign 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. S1512C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0032 ( 17 hom. )

Consequence

BRCA1
ENST00000357654.9 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:39O:1

Conservation

PhyloP100: 3.21

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031846404).

BP6

Variant 17-43074471-C-A is Benign according to our data. Variant chr17-43074471-C-A is described in ClinVar as [Benign]. Clinvar id is 41826.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074471-C-A is described in Lovd as [Benign]. Variant chr17-43074471-C-A is described in Lovd as [Pathogenic]. Variant chr17-43074471-C-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.4535G>T	p.Ser1512Ile	missense_variant	14/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.4535G>T	p.Ser1512Ile	missense_variant	14/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

343

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00381

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00237

AC:

596

AN:

251366

Hom.:

AF XY:

0.00247

AC XY:

336

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00143

Gnomad NFE exome

AF:

0.00374

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00316

AC:

4625

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

2251

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00555

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000696

Gnomad4 FIN exome

AF:

0.00137

Gnomad4 NFE exome

AF:

0.00367

Gnomad4 OTH exome

AF:

0.00273

GnomAD4 genome

AF:

0.00226

AC:

344

AN:

152284

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

153

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00382

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00391

Hom.:

Bravo

AF:

0.00241

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00215

AC:

261

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00332

ClinVar

Significance: Benign

Submissions summary: Benign:39Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:12

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 07, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 21, 1999	- -
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	literature only	Counsyl	Mar 19, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC 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 = 0.00000000000309 -
Likely benign, no assertion criteria provided	literature only	Pathway Genomics	Jul 24, 2014	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 08, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified

Benign:11Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 15, 2020	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 07, 2016	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1, c.4535G>T, p.Ser1512Ile variant has been reported in the literature in 6/2156 proband chromosomes of individuals with HBOC and sporadic breast/ ovarian cancer. It was also identified in 6/1360 of the control chromosomes evaluated (Al-Mulla_2008, Bergthorsson_2001, Young_2009, Wagner_1998, Tavtigian_2006, Phelan_2005, Sanz_2010). The variant has also been previously identified in our laboratory in 6 individuals, and was classified as benign. The variant is reported in the BIC (x58), Exome Server and BOCs databases. It is also listed in the dbSNP database as coming from a "clinical source" (ID#: rs1800744) with a MAF score of 0.001 (1000 Genomes), increasing the likelihood that this is a low frequency benign variant. The residue is not conserved in mammals, and computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. However, this information is not very predictive of pathogenicity. Functional studies examining the effect of the variant on transcriptional activation found that the variant levels were equal to or higher than that of wild type BRCA1, suggesting that it does not represent a high risk variant & is likely to have low clinical significance (Phelan_2005). Studies have also reported that p.Ser1512Ile has been found to co-occur with other known BRCA1 pathogenic variants numerous times, increasing the likelihood that this variant does not have clinical significance (Bergthorsson_2001, Tavtigian_2006, Phelan_2005). In summary, based on the above information, this variant is classified as Benign. -
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	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:5

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BRCA1: BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 06, 2016	- -

Hereditary breast ovarian cancer syndrome

Benign:5

Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 11, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 20, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 21, 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. -

BRCA1-related cancer predisposition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 27, 2024

- -

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

Dec 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

.;T;.;.;T;.;.;.;T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.84

T;T;T;T;T;T;T;T;T;T

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.032

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.9

.;L;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.1

D;N;.;D;.;N;D;D;D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0030

D;D;.;D;.;D;D;D;D;D

Sift4G

Uncertain

0.014

D;T;D;D;D;T;D;.;.;D

Polyphen

0.34, 0.88

.;B;.;.;.;.;.;.;P;.

Vest4

0.47

MVP

0.85

MPC

0.10

ClinPred

0.033

GERP RS

4.0

Varity_R

0.081

gMVP

0.41

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