chr17-43045766-C-T

Variant names:

• chr17-43045766-C-T
• rs273902776
• NM_007294.4:c.5504G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP6

The NM_007294.4(BRCA1):​c.5504G>A​(p.Arg1835Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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 O:2
• Conservation: PhyloP100: 4.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a helix (size 9) in uniprot entity BRCA1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_007294.4
• BP6: Variant 17-43045766-C-T is Benign according to our data. Variant chr17-43045766-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55604.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9, not_provided=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5504G>A	p.Arg1835Gln	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.5504G>A	p.Arg1835Gln	missense_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251334 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135856

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74268

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:2 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:5 Benign:1 Other:1

Jul 06, 2009

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 16, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2010

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 GRCh38:17:43045766:C>T was assigned evidence codes ['BP4', 'BS1_Supporting'] and an overall classification of Likely benign -

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Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Apr 10, 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 arginine with glutamine at codon 1835 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 shown the mutant protein to be partially functional in a homology-directed DNA repair assay (PMID: 26689913) and in a haploid cell proliferation assay (PMID: 30209399) and show enhanced transactivation activity (PMID: 28781887, 30458859). This variant has been reported in individuals affected with breast cancer (PMID: 17972177, 27257965, 35402282), ovarian cancer (PMID: 18627636, 24504028) and pancreatic cancer (PMID: 32980694 ). This variant has also been observed in a healthy control individual (PMID: 27403073). This variant has been identified in 9/282720 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. -

not specified Uncertain:3 Other:1

Sep 06, 2022

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.5504G>A (p.Arg1835Gln) results in a conservative amino acid change located in the BRCT domain (IPR001357) 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 3.6e-05 in 251424 control chromosomes.c.5504G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer from diverse ethnic populations without strong evidence for causality (eg. Purnomosari_2007, Thirthagiri_2008, Cunningham_2014, Zhong_2016, Zidan_2017, etc). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Functional studies demonstrated that the variant protein displayed partial or intermediate deficiency in homology-directed repair (HDR) activity with a preserved transactivation function (Findlay_2018, Lu_2015, Woods_2016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five classified the variant as VUS while one classified as likley benign. Based on the evidence outlined above, the variant was classified as VUS. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Uncertain:2

Jan 30, 2023

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 glutamine at codon 1835 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 shown the mutant protein to be partially functional in a homology-directed DNA repair assay (PMID: 26689913) and in a haploid cell proliferation assay (PMID: 30209399) and show enhanced transactivation activity (PMID: 28781887, 30458859). This variant has been reported in individuals affected with breast cancer (PMID: 17972177, 27257965, 35402282), ovarian cancer (PMID: 18627636, 24504028) and pancreatic cancer (PMID: 32980694 ). This variant has also been observed in a healthy control individual (PMID: 27403073). This variant has been identified in 9/282720 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. -

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1835Q variant (also known as c.5504G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5504. The arginine at codon 1835 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in individuals from high-risk breast/ovarian cancer families from diverse ethnic backgrounds (Zidan J et al. Breast Cancer Res. Treat. 2017 Dec;166:881-885; Liang Y et al. Med. Sci. Monit. 2018 Apr;24:2465-2475; Bhaskaran SP et al. Int. J. Cancer. 2019 Aug;145:962-973; Purnomosari D et al. Breast Cancer Res. Treat. 2007 Dec;106:297-304; Thirthagiri E et al. Breast Cancer Res. 2008 Jul;10:R59), but also in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554). This alteration was identified in a male patient with stomach cancer at age 48, and a functional comparison showed that this alteration displayed less than 70% homology-directed repair (HDR) function in comparison to wild type BRCA1 (Lu C et al. Nat Commun. 2015 Dec;6:10086). In a high throughput genome editing haploid cell survival assay, this nucleotide substitution had intermediate activity (Findlay GM et al. Nature. 2018 10;562:217-222). In addition, two different transactivation assays demonstrated that this alteration does not significantly disrupt transactivation activity (Langerud J et al. Hum. Genomics. 2018 11;12:51; Fern&aacute;ndez-Lopez JC et al. Hum. Genomics. 2019 01;13:3). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. -

Breast neoplasm Uncertain:1

Nov 01, 2015

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Uncertain:1

Dec 20, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA1 c.5504G>A at the cDNA level, p.Arg1835Gln (R1835Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). Using alternate nomenclature, this variant has been previously published as BRCA1 5623G>A. This variant was observed in individuals with personal and/or family histories of breast and/or ovarian cancer, as well as in at least one individual with gastric cancer (Purnomosari 2007, Thirthagiri 2008, Cunningham 2014, Lu 2015). Functional assays demonstrated that this variant displayed partial or intermediate deficiency in homology-directed repair activity, but retained normal transactivation function comparable to wild-type (Lu 2015, Woods 2016, Langerud 2018, Findlay 2018). BRCA1 Arg1835Gln was also identified in 1/46 healthy African-European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BRCA1 Arg1835Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain as well as a region known to interact with multiple proteins (Paul 2014, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Arg1835Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Nov 18, 2024

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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	.;T;.;T;T;T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.2	.;M;.;.;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.5	D;N;.;.;.;.;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.090	T;D;.;.;.;.;D;T
Sift4G	Uncertain	0.020	D;D;D;D;D;T;D;D
Polyphen		1.0	.;D;.;.;.;D;.;.
Vest4		0.49
MVP		0.97
MPC		0.28
ClinPred		0.60	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.47

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

Other links and lift over

dbSNP: rs273902776; hg19: chr17-41197783; COSMIC: COSV99070493;