chr17-43094021-G-A

Position:

chr17-43094021-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The ENST00000357654.9(BRCA1):c.1510C>T(p.Arg504Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R504H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

BRCA1
ENST00000357654.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:1

Conservation

PhyloP100: 2.03

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.1510C>T	p.Arg504Cys	missense_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.1510C>T	p.Arg504Cys	missense_variant	10/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251052

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135688

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461764

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000723

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:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or ovarian cancer (Ronowicz et al., 2015; Dougherty et al., 2017); Published functional studies do not demonstrate a damaging effect (Hovland et al., 2023); Also known as 1629C>T; This variant is associated with the following publications: (PMID: 15385441, 16518693, 12531920, 16267036, 15001988, 29310832, 32377563, 29884841, 15343273, 20104584, 28525389, 26219265, 31911673, 31853058, 36833189) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 13, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 22, 2023	This missense variant replaces arginine with cysteine at codon 504 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer and in a suspected hereditary breast and ovarian cancer family (PMID: 28525389, 29310832), and this variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000154). This variant has been identified in 4/282442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 30, 2023	The p.R504C variant (also known as c.1510C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1510. The arginine at codon 504 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in a Greek woman with a personal history of breast cancer (Apessos A et al. Cancer Genet 2018 Jan;220:1-12). Additionally, several papers have predicted that this alteration will affect protein function based primarily on sequence conservation through evolution (Burk-Herrick A et al. Mamm Genome. 2006 Mar; 17(3):257-70; Ramirez CJ et al. Oncogene. 2004 Mar; 23(9):1780-8; Fleming MA et al. Proc Natl Acad Sci U S A. 2003 Feb; 100(3):1151-6). However, one functional study reported that this alteration had no significant deviations in protein expression, proteasomal degradation, stability, or subcellular localization (Hovland HN et al. Genes (Basel). 2023 Jan;14(2)). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Oct 29, 2001	- -
Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 30, 2019

Variant summary: BRCA1 c.1510C>T (p.Arg504Cys) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251052 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1510C>T has been reported in the literature in individuals affected with or being tested for Hereditary Breast and Ovarian Cancer (Judkins_2005, Ronowicz_2015, Apessos_2018, Dougherty_2017). Co-occurrence with other pathogenic variant has been reported (BRCA2, p.Asn3124Ile), providing supporting evidence for a benign role (Ronowicz_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

BRCA1-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 31, 2024

This missense variant replaces arginine with cysteine at codon 504 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer and in a suspected hereditary breast and ovarian cancer family (PMID: 28525389, 29310832), and this variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000154). This variant has been identified in 4/282442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA1 p.Arg504Cys variant was not identified in affected individuals in the literature, but was identified in dbSNP (ID# rs80357445) â€šÃ„Ãºwith untested alleleâ€šÃ„Ã¹, in the Exome Variant Server ESP Project with a frequency of 0.0002 in African American alleles, in BIC 1x as a variant of unknown clinical importance, and in the LOVD database. The p.Arg504 residue is not conserved in mammals and lower organisms, and the variant amino acid (Cys) is present in cow, increasing the likelihood this is a benign variant. Computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. Two in silico evolutionary conservation studies suggest that the variant affects protein function (Fleming 2003, Ramirez 2004), while another similar study yielded inconclusive results (Burk-Herrick 2006). Additionally, the authors of these three studies note that the variant may confer oncogenic risk as it occurs within one of the BRCA1 nuclear localization sites. The variant occurs outside of the splicing consensus sequence and in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is a variant of unknown significance (VUS). -

Familial cancer of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Faculty of Pharmacy, Medical University of Gdansk

Feb 01, 2014

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 504 of the BRCA1 protein (p.Arg504Cys). This variant is present in population databases (rs80357445, gnomAD 0.004%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26219265, 28525389). ClinVar contains an entry for this variant (Variation ID: 54277). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.;.;.;T;T;.

Eigen

Benign

0.031

Eigen_PC

Benign

-0.029

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.46

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

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.6

M;M;.;.;.;.;.

MutationTaster

Benign

0.99

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

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-7.0

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

REVEL

Pathogenic

0.65

Sift

Benign

0.057

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

Sift4G

Uncertain

0.035

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

Polyphen

0.69

P;.;.;D;.;.;.

Vest4

0.37

MVP

0.88

MPC

0.16

ClinPred

0.52

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.18

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