rs799917

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_007294.4(BRCA1):c.2612C>T(p.Pro871Leu) variant causes a missense change. The variant allele was found at a frequency of 0.376 in 1,613,362 control chromosomes in the GnomAD database, including 124,333 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. P871L?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.49 ( 21276 hom., cov: 32)

Exomes 𝑓: 0.36 ( 103057 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:37O:1

Conservation

PhyloP100: 4.25

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 -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-43092918-CG-CAA is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=9.915395E-7).

BP6

Variant 17-43092919-G-A is Benign according to our data. Variant chr17-43092919-G-A is described in ClinVar as [Benign]. Clinvar id is 41812.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092919-G-A is described in Lovd as [Benign]. Variant chr17-43092919-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 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.2612C>T	p.Pro871Leu	missense_variant	10/23	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.2612C>T	p.Pro871Leu	missense_variant	10/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.487

AC:

74015

AN:

151956

Hom.:

21221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.810

Gnomad AMI

AF:

0.286

Gnomad AMR

AF:

0.390

Gnomad ASJ

AF:

0.364

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.524

Gnomad FIN

AF:

0.407

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.341

Gnomad OTH

AF:

0.459

GnomAD3 exomes

AF:

0.404

AC:

101374

AN:

251034

Hom.:

22738

AF XY:

0.402

AC XY:

54484

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.825

Gnomad AMR exome

AF:

0.348

Gnomad ASJ exome

AF:

0.377

Gnomad EAS exome

AF:

0.379

Gnomad SAS exome

AF:

0.532

Gnomad FIN exome

AF:

0.404

Gnomad NFE exome

AF:

0.334

Gnomad OTH exome

AF:

0.378

GnomAD4 exome

AF:

0.364

AC:

532630

AN:

1461288

Hom.:

103057

Cov.:

AF XY:

0.368

AC XY:

267321

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.831

Gnomad4 AMR exome

AF:

0.356

Gnomad4 ASJ exome

AF:

0.371

Gnomad4 EAS exome

AF:

0.353

Gnomad4 SAS exome

AF:

0.528

Gnomad4 FIN exome

AF:

0.397

Gnomad4 NFE exome

AF:

0.335

Gnomad4 OTH exome

AF:

0.389

GnomAD4 genome

AF:

0.487

AC:

74125

AN:

152074

Hom.:

21276

Cov.:

AF XY:

0.488

AC XY:

36241

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.811

Gnomad4 AMR

AF:

0.390

Gnomad4 ASJ

AF:

0.364

Gnomad4 EAS

AF:

0.370

Gnomad4 SAS

AF:

0.522

Gnomad4 FIN

AF:

0.407

Gnomad4 NFE

AF:

0.341

Gnomad4 OTH

AF:

0.462

Alfa

AF:

0.355

Hom.:

25841

Bravo

AF:

0.497

TwinsUK

AF:

0.347

AC:

1288

ALSPAC

AF:

0.344

AC:

1324

ESP6500AA

AF:

0.800

AC:

3525

ESP6500EA

AF:

0.336

AC:

2889

ExAC

AF:

0.410

AC:

49775

Asia WGS

AF:

0.473

AC:

1644

AN:

3478

EpiCase

AF:

0.333

EpiControl

AF:

0.342

ClinVar

Significance: Benign

Submissions summary: Benign:37Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:14

Benign, criteria provided, single submitter	clinical testing	IntelligeneCG	Aug 18, 2017	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	High frequency in a 1kG or ESP population: 33.6 %. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 22, 2011	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
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	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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 = 0.00000000000204. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.3304 (Asian), 0.1362 (African), 0.3654 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 21, 1999	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not specified

Benign:8Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 2016	p.Pro871Leu in exon 10 of BRCA1: This variant is not expected to have clinical s ignificance because it has been identified in 82% (8522/10402) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs799917}). -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2016	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 13, 2015	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	Jan 02, 2022	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 11, 2019	- -

Familial cancer of breast

Benign:2

Benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

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

May 06, 2022

- -

Breast carcinoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Faculty of Medicine Ramathibodi Hospital, Mahidol University

Apr 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.13

T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.61

T;T;T;T

MetaRNN

Benign

9.9e-7

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-3.4

N;N;.;.

MutationTaster

Benign

1.0

P;P;P;P;P;P;P;P;P;P;P;P;P;P

PrimateAI

Benign

0.42

PROVEAN

Benign

5.7

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;.;.;B

Vest4

0.31

MPC

0.082

ClinPred

0.0025

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.020

gMVP

0.084

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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