NM_007294.4:c.5506G>A

Variant names:

• chr17-43045764-C-T
• rs80356942
• NM_007294.4:c.5506G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_007294.4(BRCA1):​c.5506G>A​(p.Glu1836Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,888 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. E1836D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2
• Conservation: PhyloP100: 4.19
• Publications: 30 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 4 ACMG points.

• PM1: In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 66 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5506G>A	p.Glu1836Lys	missense_variant	Exon 23 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5506G>A	p.Glu1836Lys	missense_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251336 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3 Benign:1

Mar 01, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 12, 2024

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).In brief, for BRCA1 variants, if a variant was categorized as FUNC (functional), it was assigned BS3 evidence and no PS3 evidence, whereas if it was categorized as LOF (loss of function), the variant was assigned PS3 evidence and no BS3 evidence. Variants categorized as INT (intermediate) were left unannotated. For the BRCA1 combining criteria, greater than or equal to 1 criteria of strong benign evidence was enough to reclassify the VUS as Likely Benign. This variant GRCh37:17:41197781:C>T was assigned evidence codes ['BS3'] and an overall classification of Likely Benign -

Dec 01, 2023

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 glutamic acid with lysine at codon 1836 of the BRCA1 protein. Computational prediction tool 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 discrepant findings on variant protein impacts, including modest (PMID: 21473589) to severe disruption (PMID: 20516115) in phosphopeptide binding activity, greater than 50% of wild-type transcriptional activation (PMID: 20516115), and normal function in complementing BRCA1 deficiency and rescue cell proliferation in haploid cells (PMID: 30209399). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

May 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1836K variant (also known as c.5506G>A and 5625G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5506. The glutamic acid at codon 1836 is replaced by lysine, an amino acid with similar properties. One study, which assessed the effect of BRCT missense alterations by structure and sequence based computational analysis, found this alteration to have a probability of affecting structure and function of 0.48 and 0.42, using two sets of analytic features. Additionally, refined sequence based analysis predicted this alteration to affect function (Williams RS et al. J. Biol. Chem. 2003 Dec; 278(52):53007-16). Using several different structural and functional assays, another study found this alteration to be structurally stable; however, they did predict compromised binding activity and specificity, with less than 10% of wild type for both parameters, and found transcriptional activation to be at 55% of wild type, resulting in a classification of uncertain significance for this alteration (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90). Additionally, while one study suggested that this alteration could perturb phosphopeptide recognition and binding (Campbell SJ et al. Structure 2010 Feb; 18(2):167-76), other studies showed that this alteration does not dramatically affect function (Coquelle N et al. Biochemistry 2011 May; 50(21):4579-89; Findlay GM et al. Nature, 2018 Oct;562:217-222). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Jun 28, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 1836 of the BRCA1 protein. Computational prediction tool 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 discrepant findings on variant protein impacts, including modest (PMID: 21473589) to severe disruption (PMID: 20516115) in phosphopeptide binding activity, greater than 50% of wild-type transcriptional activation (PMID: 20516115), and normal function in complementing BRCA1 deficiency and rescue cell proliferation in haploid cells (PMID: 30209399). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Breast and/or ovarian cancer Uncertain:1 Benign:1

Sep 02, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2013

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1

Jan 20, 2025

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.5506G>A (p.Glu1836Lys) results in a conservative amino acid change located in the BRCT domain profile (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251336 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5506G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. Experimental studies provide conflicting reports regarding the functional outcome of this variant (e.g. Findlay_2018, Lee_2010, Carvalho_2014). The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 20516115, 24845084). ClinVar contains an entry for this variant (Variation ID: 55605). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group S Uncertain:1

Oct 16, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jun 02, 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; Published functional studies are inconclusive: discrepant phosphopeptide binding and transcriptional activation activity, but normal protein folding, homologous recombination activity, and cell survival (Lee et al., 2010; Coquelle et al., 2011; Carvalho et al., 2014; Woods et al., 2016; Findlay et al., 2018; Fernandes et al., 2019; Petitalot et al., 2019; Iversen et al., 2022); Also known as 5625G>A; This variant is associated with the following publications: (PMID: 20159462, 14534301, 24845084, 30209399, 22154951, 28781887, 30765603, 30257991, 21473589, 20516115, 36530327, 29884841, 32377563, 35665744, 25348405) -

Hereditary breast ovarian cancer syndrome Uncertain:1

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1836 of the BRCA1 protein (p.Glu1836Lys). This variant is present in population databases (rs80356942, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 55605). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 20516115, 21473589, 24845084, 30209399, 30765603). 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	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	.;T;.;T;T;T;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.2	.;M;.;.;.;.;.;.
PhyloP100		4.2
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.6	D;N;.;.;.;.;N;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.024	D;D;.;.;.;.;D;D
Sift4G	Benign	0.10	T;D;D;D;D;T;D;T
Polyphen		1.0, 0.97	.;D;.;.;.;D;.;.
Vest4		0.80
MVP		0.94
MPC		0.43
ClinPred		0.85	D
GERP RS		5.3
Varity_R		0.61
gMVP		0.45
Mutation Taster		=0/100	disease causing

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: rs80356942; hg19: chr17-41197781;