chr17-43091783-C-T

Variant names:

Variant summary

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

The NM_007294.4(BRCA1):c.3748G>A(p.Glu1250Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:29O:1

Conservation

PhyloP100: 0.505

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16408089).

BP6

Variant 17-43091783-C-T is Benign according to our data. Variant chr17-43091783-C-T is described in ClinVar as [Benign]. Clinvar id is 54987.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091783-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.3748G>A	p.Glu1250Lys	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.3748G>A	p.Glu1250Lys	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251234

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000322

AC:

470

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

220

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.000402

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000158

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000367

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:29Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:7Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 30/66732 European; ClinVar: 6 B/LB -

Jan 23, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 20, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 24, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:8

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 09, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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 = 0.000000204 -

Mar 17, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 06, 2015

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:4

Jul 12, 2017

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 13, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary breast ovarian cancer syndrome

Benign:3

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant Summary: c.3748G>A is a missense mutation that occurs at a non-conserved position, resulting in a change from medium size and acidic (E) to large size and basic (K) residue, and 3/4 in silico tools predict a benign outcome (SNPs&Go not captured here due to low reliability index). A heatmap of the unsupervised cluster analysis of several assays carried out by Loke et al 2015, showed that this missense variant clusters with WT BRCA1, Bouwman et al 2013 showed that the E1250K mutant protein behaves similarly to WT in a cisplatin (anticancer drug) sensitivity assay, and other studies have shown that it does not alter splicing and the protein is expressed at normal levels (Anczukow et al 2008). Lindor_2012 and Pavlicek_2004 predict that the variant is neutral based on in silico prediction models.The observed allele frequency in controls is 39/127500 (1/3269; 0.03%), which is lower than the maximal expected allele frequency of 1/1000 for a pathogenic BRCA1 variant. However, UMD cites a pathogenic BRCA2 co-occurrence in 1 individual, and BIC cites the variant to co-occur with pathogenic BRCA1 co-occurrences in 2 individuals (p.Tyr1563Ter and p.Trp1508Ter; also cited in Tavtigian et al 2006) and a BRCA2 pathogenic co-occurrence (p.Lys936_Gln937?fs) in 1 individual. Further more, in one HBOC family, the variant of interest did not co-segregate with disease (Jara_BRCA1_Biol Res_2004). These numerous pathogenic co-occurrences and lack of co-segregation with disease are a strong indication of a benign outcome for this missense BRCA1 variant. Additionally, numerous reputable databases and clinical diagnostic labs have classified this variant as benign. Taken together, this missense BRCA1 mutation is a normal variant and has been classified as benign. -

Breast and/or ovarian cancer

Benign:2

Nov 07, 2013

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 08, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA1-related cancer predisposition

Benign:1

Sep 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast neoplasm

Benign:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Glu1250Lys variant was identified in at least 6 of 111702 proband chromosomes (frequency: 0.0001) from individuals or families with breast or ovarian cancer and was present in 2 of 2508 control chromosomes (frequency: 0.001) from healthy individuals (Diez 2003, Grudinina 2005, Jara 2004, Judkins 2005, Osorio 2007, Salazar 2006). The variant was also identified in dbSNP (ID: rs28897686) â€šÃ„ÃºWith pathogenic alleleâ€šÃ„Ã¹, HGMD, LOVD, the BIC database (20X with no clinical importance), and UMD (14X as a neutral variant). In UMD, one sample found the variant co-occurring with a pathogenic mutation in BRCA2 (c.368_372delAAATG (p.Lys123ArgfsX5)), increasing the likelihood that the p.Glu1250Lys variant may not have clinical importance. The p.Glu1250 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact of the p.Glu1250Lys variant to the protein; this information is not very predictive of pathogenicity. The variant was listed in the NHLBI Exome Sequencing Project in 4 of 130006 alleles (frequency: 0.0003), increasing the likelihood that this may represent a low frequency benign variant. One study identified the variant co-occurring in trans with two different deleterious BRCA1 mutations, increasing the likelihood that the variant does not have clinical significance (Judkins 2005). In addition, one functional study and three in silico studies all found the variant to be neutral (Bouwman 2013, Abkevich 2004 15235020, Lindor 2012, Tavtigian 2006). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.;.;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.082

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.6

L;L;.;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.71

N;N;N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.048

D;T;T;T

Polyphen

0.84

P;.;.;B

Vest4

0.31

MVP

0.64

MPC

0.24

ClinPred

0.037

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.054

gMVP

0.16

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