17-43074486-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4BP6_Very_Strong

The NM_007294.4(BRCA1):c.4520G>C(p.Arg1507Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R1507S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:8B:6

Conservation

PhyloP100: -0.0770

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia, complementation group S
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 4
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31684804).

BP6

Variant 17-43074486-C-G is Benign according to our data. Variant chr17-43074486-C-G is described in ClinVar as Benign. ClinVar VariationId is 41825.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.4520G>C	p.Arg1507Thr	missense_variant	Exon 14 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.4520G>C	p.Arg1507Thr	missense_variant	Exon 14 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

251338

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1111954

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:8Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2Benign:2

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 05, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

a point mutation in the BRCA1 gene (c.4583G>C) which results in the substitution of threonine for arginine at position 1528. This mutation is considered as a variant of unknown significance. Further genetic testing might be considered. -

Jun 18, 2019

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 = 0.000442 -

Mar 02, 2020

BRCAlab, Lund University

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:2Benign:1

Nov 01, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted BRCA1 c.4520G>C at the cDNA level, p.Arg1507Thr (R1507T) at the protein level, and results in the change of an Arginine to a Threonine (AGG>ACG). Using alternate nomenclature, this variant would be defined as BRCA1 4639G>C. This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). BRCA1 Arg1507Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Arg1507Thr occurs at a position that is not conserved and is located in a region known for interaction with multiple proteins (Narod 2004, Clark 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Arg1507Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

May 21, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Dec 20, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Apr 29, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with threonine at codon 1507 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have reported that this variant does not impact BRCA1 function in a transcription activation assay and a murine homology-mediated repair assay (PMID: 28781187, 32546644). This variant has been reported in individuals and families affected with breast and/or ovarian cancer and in unaffected individuals (PMID: 16267036, 33471991; Leiden Open Variation Database DB-ID BRCA1_001353; Color internal data) and prostate cancer (PMID: 29368341; Color internal data). A multifactorial analysis has reported likelihood ratios for pathogenicity of 0.21, 1.1391 and 0.0906 based on tumor pathology, co-occurrence and family history, respectively (PMID: 31131967). This variant has been identified in 7/251338 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the available evidence indicates that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Oct 28, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS3, BP1_Strong, BP5_Strong c.4520G>C, located in exon 14 (15 according to BIC nomenclature) of the BRCA1 gene, is predicted to result in the substitution of arginine by threonine at codon 1507, p.(Arg1507Thr). This position is outside a (potentially) clinically important functional domain and, moreover, the SpliceAI algorithm predicts no significant impact on splicing (BP1_Strong). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.545) is indeterminate regarding the effect that it may have on protein function according Pejaver 2022 thresholds (PMID: 36413997). This variant is found in 3/30524 with a filter allele frequency of 0.0014% at 99% confidence in the gnomAD v2.1.1 database (South Asian exome only non-cancer data set). Reported by two calibrated studies to affect protein function similar to benign control variants (PMIDs:32546644, 30765603)(BS3). Published clinical data for a multifactorial likelihood analysis (PMID: 31131967) showed a combined LR indicative of strong evidence towards benignity (LR 0.022), based on severity of summary family histories (LR 0.09), tumour characteristics (LR 0.21), and co-occurrence (LR 1.139)(BP5_Strong). The variant is present in ClinVar (6x uncertain significance, 3x likely benign, 1x benign) and LOVD (3x VUS, 2x not classified) databases and classified as benign by BRCA Exchange database (‘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 = 0.000442’).Based on currently available information, the variant c.4520G>C is classified as a benign variant to ClinGen- BRCA1 and BRCA2 Guidelines version 1.0.0. -

not specified

Uncertain:1

Mar 03, 2020

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA1 c.4520G>C (p.Arg1507Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251338 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4520G>C has been reported in the literature in individuals affected with prostate cancer (IsaacssonVelho_2018) and in at least one individual undergoing genetic testing for Hereditary Breast and Ovarian Cancer (Judkins_2005). The variant was also reported in an individual from a cohort selected for atherosclerosis phenotypes (Johnston_2012). These reports do not provide strong evidence for causality and thus do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several publications report experimental evidence evaluating an impact on protein function. No damaging effects for the variant were observed on transcriptional activity as measured in assays using yeast cells (Woods_2016, Fernandes_2019). Four clinical diagnostic laboratories and one expert panel have submitted clinical significance assesments for this variant to ClinVar (evaluation after 2014) and cite the variant as uncertain significance (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Breast and/or ovarian cancer

Uncertain:1

Nov 11, 2020

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BRCA1-related cancer predisposition

Uncertain:1

May 30, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with threonine at codon 1507 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in a transcription activation assay and a murine homology-mediated repair assay (PMID: 28781187, 32546644). This variant has been reported in individuals and families affected with breast and/or ovarian cancer and in unaffected individuals (PMID: 16267036, 33471991; Leiden Open Variation Database DB-ID BRCA1_001353; Color internal data) and prostate cancer (PMID: 29368341; Color internal data). A multifactorial analysis has reported likelihood ratios for pathogenicity of 0.21, 1.1391 and 0.0906 based on tumor pathology, co-occurrence and family history, respectively (PMID: 31131967). This variant has been identified in 7/251338 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the available evidence indicates that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary breast ovarian cancer syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

0.0086

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

2.5

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.27

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

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.059

LIST_S2

Uncertain

0.89

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

M_CAP

Pathogenic

0.65

MetaRNN

Benign

0.32

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

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.9

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

PhyloP100

-0.077

PrimateAI

Benign

0.26

PROVEAN

Benign

-2.2

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

REVEL

Uncertain

0.55

Sift

Uncertain

0.010

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

Sift4G

Benign

0.093

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

Polyphen

0.094, 0.27

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

Vest4

0.50

MVP

0.74

MPC

0.13

ClinPred

0.082

GERP RS

0.85

Varity_R

0.039

gMVP

0.25

Mutation Taster

=60/40

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over