17-43074486-C-G

Position:

chr17-43074486-C-G

Variant summary

Our verdict is Benign. Variant got -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. 13/21 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. R1507R) has been classified as Likely benign.

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:5

Conservation

PhyloP100: -0.0770

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 -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 id is 41825.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074486-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.4520G>C	p.Arg1507Thr	missense_variant	14/23	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.4520G>C	p.Arg1507Thr	missense_variant	14/23	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

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251338

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135834

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 SAS exome

AF:

0.0000980

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:8Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	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 -
Uncertain significance, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	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. -

not provided

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 21, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2016	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. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 25, 2023	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 03, 2020

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 11, 2020

- -

BRCA1-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 30, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

- -

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

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;.;.;.;.;.;.;.

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

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