chr17-43074406-C-T

Position:

chr17-43074406-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_007294.4(BRCA1):c.4600G>A(p.Val1534Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,614,162 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. VE1534A?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:25O:1

Conservation

PhyloP100: -2.02

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01621309).

BP6

Variant 17-43074406-C-T is Benign according to our data. Variant chr17-43074406-C-T is described in ClinVar as [Benign]. Clinvar id is 55235.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074406-C-T is described in Lovd as [Benign]. Variant chr17-43074406-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.4600G>A	p.Val1534Met	missense_variant	14/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.4600G>A	p.Val1534Met	missense_variant	14/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00134

AC:

204

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00417

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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:

0.000147

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000386

AC:

AN:

251360

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00461

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000224

AC:

327

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

141

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00529

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000926

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.00134

AC:

204

AN:

152318

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00416

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000280

Hom.:

Bravo

AF:

0.00176

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:25Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:8Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 01, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Val1534Met variant has been observed in the literature in 5/5288 proband chromosomes of individuals with hereditary breast cancer, ovarian cancer and prostate cancer. It was not detected in any of the 360 control chromosomes evaluated (Abkevich 2004, Carvalho 2007, Chenevix-Trench 2006, Hondow 2011, Iversen 2011, Leongamornlert 2012, Velasco 2005, Millot 2012). The variant was also observed by our lab in one unaffected individual in a family where a different pathogenic variant was reported, increasing the likelihood this variant does not have clinical significance. The variant was also identified in ClinVar by GeneDx (benign), and by Invitae and ITMI (significance not provided). It is listed in the dbSNP database (ID#: rs55815649) as coming from a clinical source with a global minor allele frequency (MAF) of 0.001, having been observed thrice in 3,000 chromosomes. It has been reported in the UMD (x8 as neutral), BIC (x26 as VUS), and EVS (ACMG 3) databases. This residue is not conserved in mammals and the variant amino acid Methionine (Met) is present in the dog. Computational analyses (PolyPhen, SIFT, AlignGVGD) does not predict any effect on the protein function, increasing the likelihood this variant does not have functional significance. In addition, in one of the functional studies that measured the transactivation activity of BRCA1, the activity level of the variant was comparable to the wild-type protein in mammalian cells (Carvalho 2007). In summary, based on the above information, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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: ExAC: 0.5% (52/10406) African chromosomes; ClinVar: 2 labs classify as LB; 5 papers describe as nonpathogenic -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:5

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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 = 0.000000000074 -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Benign, criteria provided, single submitter	literature only	Counsyl	May 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Apr 08, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 23, 2020	- -
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	Oct 15, 2015	- -

Hereditary breast ovarian cancer syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2014	Variant summary: (1) Variant is found in a non-conserved region with a high prevalence in control individuals (22/7,595), (2) Variant is reported to co-occur with other potentially pathogenic variants in BRCA1 (p.Glu1413AspfsX2, 2 - p.Gln1240X) and 1 BRCA2 (p.Ile1874ArgfsX34)(UMD), (3) Functional studies suggest comparable activity levels to wild type (Carvalho_BRCA1_CR_2007) and (4) multiple databases and publications classify variant as benign/neutral (Emory genetics, UMD, ARUP, Easton_2007, Carvalho_2007, Chenevix-Trench_2006 and Lindor_2012) . -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	BRCA1: BP4, BS1, BS2 -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Benign

0.67

DANN

Benign

0.87

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.73

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

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.016

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

MetaSVM

Benign

-0.68

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.53

N;N;.;N;.;N;N;N;N;N

REVEL

Uncertain

0.58

Sift

Benign

0.18

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

Sift4G

Benign

0.23

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

Polyphen

0.070, 0.062

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

Vest4

0.10

MVP

0.57

MPC

0.081

ClinPred

0.0085

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.016

gMVP

0.13

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