rs80357445

Variant names:

• chr17-43094021-G-A
• rs80357445
• NM_007294.4:c.1510C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43094021-G-A
• chr17-43094021-G-C
• chr17-43094021-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_007294.4(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. R504G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:2
• Conservation: PhyloP100: 2.03
• Publications: 16 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1510C>T	p.Arg504Cys	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.1510C>T	p.Arg504Cys	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152036 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251052 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461764 Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74390

African (AFR) AF: 0.0000723 AC: 3 AN: 41510

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000428 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Nov 03, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.1510C>T (p.Arg504Cys) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 26219265 (2015), 28525389 (2017), 29310832 (2018)). In one individual with breast cancer, this variant was reported to co-occur with a pathogenic variant in the BRCA2 gene, which suggests this variant is not the primary cause of disease (PMID: 26219265 (2015)). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease (PMID: 36833189 (2023)). The frequency of this variant in the general population, 0.000059 (3/50674 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Apr 24, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:1

Mar 02, 2020

BRCAlab, Lund University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 29, 2001

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 17, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Apr 02, 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 cysteine at codon 504 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. 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. -

Apr 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 an individual diagnosed with 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified Uncertain:1

Aug 30, 2019

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.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

May 31, 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 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

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Arg504Cys variant was not identified in affected individuals in the literature, but was identified in dbSNP (ID# rs80357445) “with untested allele”, 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

Feb 01, 2014

Faculty of Pharmacy, Medical University of Gdansk

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 36833189). 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	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
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	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.6	M;M;.;.;.;.;.
PhyloP100		2.0
PrimateAI	Benign	0.26	T
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	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.18
gMVP		0.16
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs80357445; hg19: chr17-41246038; COSMIC: COSV100525342; COSMIC: COSV100525342;