rs80357867

Positions:

chr17-43063345-TTTTC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_007294.4(BRCA1):c.5177_5180del(p.Arg1726LysfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,610,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:29

Conservation

PhyloP100: 3.31

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-43063345-TTTTC-T is Pathogenic according to our data. Variant chr17-43063345-TTTTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 37644.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063345-TTTTC-T is described in Lovd as [Pathogenic]. Variant chr17-43063345-TTTTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.5177_5180del	p.Arg1726LysfsTer3	frameshift_variant	18/23	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.5177_5180del	p.Arg1726LysfsTer3	frameshift_variant	18/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00000797

AC:

AN:

251090

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458668

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

725950

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:29

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 10, 2023	This variant deletes 4 nucleotides in exon 18 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 5296del4 based on Breast Cancer Information Core (BIC) nomenclature. This variant has been reported in multiple individuals affected with breast and/or ovarian cancer, as well as individuals from hereditary breast and ovarian cancer families (PMID: 18042939, 22923021, 23397983, 24504028, 26287763, 27425403, 27469594, 28008555, 28324225, 29907814, 33606809, 34717758). In a large breast cancer case-control study, this variant has been observed in 17/60449 cases and 6/53455 controls (PMID: 33471991). This variant has also been identified in 2/251090 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 18, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 30, 1999	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 28, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 12, 2023	Criteria applied: PVS1,PS4_MOD,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	The c.5177_5180del ;p.(Arg1726Lysfs*3) is a null frameshift variant (NMD) in the BRCA1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 37644; PMID: 9150171; PMID: 22923021; PMID: 23397983; PMID: 24504028; PMID: 26287763; PMID: 27831900)PS4. The variant is present at low allele frequencies population databases (rs80357867 – gnomAD 0.00006572%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	Sep 05, 2024	Null variant (frame-shift) in gene BRCA1, predicted to cause NMD. Loss-of-function is a known mechanism of disease (gene has 3 663 reported pathogenic LOF variants). The exon affects 1 functional domain: UniProt protein BRCA1_HUMAN domain 'BRCT 1'. The exon contains 46 pathogenic variants. The truncated region contains 450 pathogenic variants (PVS1). Combined evidence strength is Very Strong (score = 12).Very Strong: ClinVar classifies this variant as Pathogenic, 3 stars (reviewed Jul '24, 28 submissions of which 4 are from high confidence submitters) (PP5). GnomAD genomes homozygous allele count = 0 is less than 2 for AD/AR gene BRCA1, good gnomAD genomes coverage = 31.0.GnomAD exomes homozygous allele count = 0 is less than 2 for AD/AR gene BRCA1, good gnomAD exomes coverage = 31.5 (PM2). We observed this variant in a 61-year-old female patient with Breast-ovarian cancer, familial, 1. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 28, 2023	The BRCA1 c.5177_5180del (p.Arg1726Lysfs*3) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals/families with breast and/or ovarian cancer (PMID: 34717758 (2021), 33646313 (2021), 32772980 (2020), 26287763 (2015), 25452441 (2015), 24504028 (2014), 23397983 (2014), 22923021 (2012)), including male breast cancer (PMID: 28008555 (2017)), as well as an individual unaffected by cancer (PMID: 27831900 (2016)). The frequency of this variant in the general population, 0.000008 (2/251090 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in several individuals and families with breast and/or ovarian cancer (Gao 1997, Tai 2007, Song 2014, Pal 2015, Ewald 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 5296_5299delGAAA; This variant is associated with the following publications: (PMID: 25452441, 24504028, 9150171, 21232165, 24728189, 16234499, 25330149, 9667259, 26287763, 27469594, 25556971, 26843898, 22923021, 25085752, 23397983, 27303907, 28008555, 28127413, 28785956, 27831900, 28324225, 18042939, 27425403, 29907814, 29161300, 30322717, 26848151, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This is a deletion of 4 base pairs from exon 18 of the BRCA1 mRNA (c.5177_5180delGAAA), causing a frameshift at codon 1726. This deletion creates a premature translation stop signal 3 amino acid residues later and is expected to result in an absent or disrupted protein product. This variant is also known as 5296del4 in the literature and has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 9150171, 22923021, 24504028). The mutation database ClinVar contains entries for this variant (Variation ID: 37644). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -

Hereditary breast ovarian cancer syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Arg1726Lysfs*3) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357975, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150171, 22923021, 23397983, 24504028, 26287763, 27831900). This variant is also known as 5296del4. ClinVar contains an entry for this variant (Variation ID: 37644). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2018	Variant summary: BRCA1 c.5177_5180delGAAA (p.Arg1726LysfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Met1728fsX2 and p.Gln1747X). The variant allele was found at a frequency of 8e-06 in 250304 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (8e-06 vs 0.001), allowing no conclusion about variant significance. The c.5177_5180delGAAA variant has been reported in the literature in numerous individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 15, 2021	The p.Arg1726LysfsX3 variant in BRCA1 has been reported in >30 individuals with BRCA1-associated cancers (Gao 1997 PMID:9150171, Cunningham 2014 PMID:24504028, Stegel 2011 PMID:21232165, Trujillano 2015 PMID:25556971, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). It has also been identified in 0.002% (1/41446) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1726 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variant ID 37644). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 05, 2018	The c.5177_5180del (p.Arg1726Lysfs3) variant of the BRCA1 gene creates an early stop codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 9150171, 18042939, 21232165, 22333603, 22923021, 23397983, 24504028, 24728189, 25556971, 26287763, 27303907, 27831900, 28008555, 28324225). This variant has been identified in 2/251090 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in BRCA1 are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, the c.5177_5180del (p.Arg1726Lysfs3) variant of the BRCA1 gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 18, 2021	The c.5177_5180delGAAA pathogenic mutation, located in coding exon 17 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 5177 to 5180, causing a translational frameshift with a predicted alternate stop codon (p.R1726Kfs*3). This mutation has been reported in multiple individuals and families of various ethnicities with clinical histories suggestive of hereditary breast and ovarian cancer including early-onset breast cancer (earliest published age of onset is 24), bilateral breast cancer, triple-negative breast cancer, ovarian cancer, and male breast cancer (Gao Q et al. Am. J. Hum. Genet. 1997 May;60:1233-6; Tai YC et al. J. Natl. Cancer Inst. 2007 Dec;99:1811-4; Robertson L et al. Br. J. Cancer 2012 Mar;106:1234-8; Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Ewald IP et al. Genet. Mol. Biol. 2016 Apr-Jun;39:223-31; Natarajan P et al. Sci. Transl. Med. 2016 Nov;8:364ra151; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238; Sandoval RL et al. PLoS One. 2021 Feb;16:e0247363). Of note, this alteration is also designated as 5296del4 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 17, 2022	This variant deletes 4 nucleotides in exon 18 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 5296del4 based on Breast Cancer Information Core (BIC) nomenclature. This variant has been reported in multiple individuals affected with breast and/or ovarian cancer, as well as individuals from hereditary breast and ovarian cancer families (PMID: 18042939, 22923021, 23397983, 24504028, 26287763, 27425403, 27469594, 28008555, 28324225, 29907814, 33606809, 34717758). In a large breast cancer case-control study, this variant has been observed in 17/60449 cases and 6/53455 controls (PMID: 33471991). This variant has also been identified in 2/251090 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Rhabdomyosarcoma

Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Sep 01, 2020

- -

Ovarian neoplasm

Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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