rs28897676

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_007294.4(BRCA1):c.1486C>T(p.Arg496Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 1,613,802 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R496H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:25

Conservation

PhyloP100: -0.232

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11185163).

BP6

Variant 17-43094045-G-A is Benign according to our data. Variant chr17-43094045-G-A is described in ClinVar as [Benign]. Clinvar id is 37416.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094045-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.1486C>T	p.Arg496Cys	missense_variant	10/23	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.1486C>T	p.Arg496Cys	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000235

AC:

AN:

251190

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000309

AC:

451

AN:

1461718

Hom.:

Cov.:

AF XY:

0.000281

AC XY:

204

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000354

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000171

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000343

Hom.:

Bravo

AF:

0.000268

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:25

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:10

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2018	- -
Benign, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2016	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 03, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Classified in ClinVar with 3 stars as Benign by ENIGMA (expert panel), Invitae, GeneDx, Ambry and as VUS by CSER and BIC. It has a max MAF of 0.026% in ExAC (3 Latino alleles). The AA is not conserved and only mammals have this region, 6 of which have a Cys at this position. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 23, 2018	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 16, 2014	- -

Breast and/or ovarian cancer

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Uncertain significance, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Oct 10, 2001	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 01, 2021	- -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:2

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 = 0.000891 -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	BRCA1: BP1, BS3:Moderate, BS4 -

Hereditary breast ovarian cancer syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 16, 2024	The missense variant NM_007294.4(BRCA1):c.1486C>T (p.Arg496Cys) has been reported to ClinVar as Benign with a status of (3 stars) reviewed by expert panel (Variation ID 37416 as of 2024-08-01).The p.Arg496Cys missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The cysteine residue at codon 496 of BRCA1 is present in Bushbaby and 6 other mammalian species. The nucleotide c.1486 in BRCA1 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Benign. -

BRCA1-related cancer predisposition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 10, 2021

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Arg496Cys variant is identified in the literature in 6 out of 7356 proband chromosomes (frequency 0.001) with breast and ovarian cancers, however a limited number of control chromosomes were analyzed (0 out of 700, frequency=0), and so the frequency of this variant in the general population could not adequately be assessesed (Infante 2006, Chenevix-Trench 2006, Van-Hassel 2010, Borg 2010, German consortium 2002, Arnold 2002). It is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897676) with an average heterozygosity of 0.000+/-0.015 from one population. The BIC database reports this variant 46X with unknown clinical importance. It is reported 52 times in the myriad database "in trans" and therefore likely to be neutral (Chenevix-Trench 2006). In the UMD database, this variant has been identified in 12 individuals with breast or ovarian cancers, and in 4 of these cases a second pathogenic BRCA1 or BRCA2 mutation was also detected, therefore increasing the likelihood this variant is benign. The p.Arg496 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein, and other in silico analysis do not show any impact on the function (Lovelock 2007, Lindor 2011, Capanu 2011, Waddel 2008, Lee 2008, Mark_2005_15571721, Judkins_2005_16267036). Another variant at the same location, p.Arg496His, is also found 12 times in UMD database, with a second pathogenic variant co-occurring in 5 individuals with beast and ovarian cancer phenotype, decreasing the likelihood the p.Arg496Cys variant has clinical significance. In summary, based upon the above information, this variant is classified as benign. -

BRCA1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 2019

This 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Uncertain

0.010

CADD

Benign

4.7

DANN

Benign

0.72

DEOGEN2

Benign

0.25

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

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.083

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D

M_CAP

Benign

0.042

MetaRNN

Benign

0.11

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

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.1

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

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-3.7

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

REVEL

Uncertain

0.57

Sift

Benign

0.13

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

Sift4G

Benign

0.22

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

Polyphen

0.0040

B;.;.;B;.;.;.

Vest4

0.30

MVP

0.56

MPC

0.11

ClinPred

0.011

GERP RS

-0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.11

gMVP

0.071

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