rs80357701

Positions:

• chr17-43092196-TCTTG-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.3331_3334del​(p.Gln1111AsnfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,164 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:36 O:1
• Conservation: PhyloP100: 1.86

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-43092196-TCTTG-T is Pathogenic according to our data. Variant chr17-43092196-TCTTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 37523.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092196-TCTTG-T is described in Lovd as [Pathogenic]. Variant chr17-43092196-TCTTG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3331_3334del	p.Gln1111AsnfsTer5	frameshift_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.3331_3334del	p.Gln1111AsnfsTer5	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460984 Hom.: 0 AF XY: 0.00000826 AC XY: 6 AN XY: 726808

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: 0.0000117

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:36 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:19

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	The c.3331_3334del;p.(Gln1111Asnfs*5) 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: 37523; PMID: 24742220; 24916970; PMID: 27741520; PMID: 29161300) - PS4. This variant is not present in population databases (rs80357701- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 28, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS3, PS4_STR PM2_SUP -
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, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 15, 2023	This variant deletes 4 nucleotides in exon 10 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 reported as a common cause of hereditary breast and ovarian cancer in Latin American populations (PMID: 17080309, 27286788, 29088781). This variant has not been identified 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	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 27, 2018	The c.3331_3334delCAAG (p. Gln1111Asnfs*5) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 8933332, 17080309, 21324516, 27081505, 27914478). This variant is absent from large databases of genetic variation in the general population. Therefore, the c.3331_3334delCAAG (p. Gln1111Asnfs*5) variant in the BRCA1 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 18, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 04, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	case-control	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	May 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 27, 2023	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PP1 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 18, 2019	This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with breast, ovarian, and gastric cancer (PMID: 30535581 (2019), 30322717 (2018), 30078507 (2018), 29161300 (2017), 28024868 (2017), and 23683081 (2013)). It is also described as a founder mutation in Colombian, Chilean, Spanish, and Portuguese populations in the published literature (PMID: 29088781 (2017), 28680148 (2017), 21603858 (2012)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This is a deletion of 4 base pairs from exon 10 of the BRCA1 mRNA (c.3331_3334delCAAG), which results in frameshift at codon 1111 and creation of a novel stop codon 5 amino acid residues later. It is expected to result in a truncated, non-functional protein. This variant has also been described in mutation databases as 3450del4. The mutation database ClinVar contains entries for this variant (Variation ID: 37523). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2023	Reported in patients with personal and/or family histories of breast and/or ovarian cancer, segregating with cancer in at least one family, and likely represents a Spanish founder variant (Durocher 1996, Panguluri 1999, Torres 2007, Zhang 2011, Rodriguez 2012, Blay 2013, Laraqui 2013, Felix 2014, Peixoto 2014, Fernandes 2016, Maistro 2016); 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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3450del4, 3450delCAAG, and c.3450_3453delCAAG; This variant is associated with the following publications: (PMID: 24742220, 11376024, 22044689, 23683081, 11030417, 11857748, 24916970, 17080309, 31921681, 27741520, 34657373, 34413315, 32438681, 28888541, 17591843, 21324516, 24764757, 27081505, 7493024, 19377795, 21603858, 23289006, 20104584, 10480351, 26071757, 27469594, 27425403, 27914478, 28127413, 28024868, 27286788, 8933332, 19098453, 29101607, 29088781, 28477318, 29339979, 29907814, 28680148, 29161300, 30606148, 30078507, 30322717, 30535581, 30736435, 31447099, 32039725, 33646313, 32341426, 32719484, 33087180, 31892343, 33758026, 34645131, 35264596, 34567246, 35464868) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change creates a premature translational stop signal (p.Gln1111Asnfs*5) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 22044689, 24742220, 24916970). It is commonly reported in individuals of Portuguese ancestry (PMID: 22044689, 24742220, 24916970). This variant is also known as 3450del4 and 3450delCAAG. ClinVar contains an entry for this variant (Variation ID: 37523). 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 22, 2017	Variant summary: The BRCA1 c.3331_3334delCAAG (p.Gln1111Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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., c.3342_3345delAGAA [p.Glu1115X], c.3351dupT [p.Gln1118fs). One in silico tool, Mutation Taster, predicts a damaging outcome for this variant. This variant is absent in the large control population database ExAC (0/121128 control chromosomes). Multiple clinical diagnostic laboratories/reputable databases (13 in total) classified this variant as pathogenic. Additionally, several publications have identified the variant in affected individuals and co-segregation of the variant with disease has been established through family studies. Taken together, this variant is classified as pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant classified as Pathogenic and reported on 09-07-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 22, 2023	PVS1, PS4 -
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 04, 2021	The c.3331_3334delCAAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 3331 to 3334, causing a translational frameshift with a predicted alternate stop codon (p.Q1111Nfs*5). This mutation has been reported in multiple families with hereditary breast and ovarian cancer (Durocher F et al. J. Med. Genet. 1996 Oct;33:814-9; Felix GE et al. Hum. Genome Var. 2014 Oct;1:14012; Maistro S et al. BMC Cancer. 2016 Dec;16:934; Gabaldo Barrios X et al. Fam. Cancer. 2017 10;16:477-489), and several studies have described this alteration as a founder mutation in the Colombian and Chilean populations (Durocher F et al. J. Med. Genet. 1996 Oct;33:814-9; Torres D et al. Breast Cancer Res Treat. 2007 Jun;103:225-32; Rodriguez A et al. Gynecol. Oncol. 2012 Feb;124:236-43; Alvarez C et al. Oncotarget. 2017 Sep;8:74233-74243). The c.3331_3334delCAAG pathogenic mutation has also been reported in a 54-year-old male diagnosed with diffuse gastric cancer who did not meet hereditary diffuse gastric cancer clinical criteria and had negative CDH1 gene analysis (Sahasrabudhe R et al. Gastroenterology. 2017 Apr;152:983-986.e6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 3450del4 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	Dec 14, 2022	This variant deletes 4 nucleotides in exon 10 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 reported as a common cause of hereditary breast and ovarian cancer in Latin American populations (PMID: 17080309, 27286788, 29088781). This variant has not been identified 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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 26, 2022

- -

Breast neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

-

- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 17, 2022

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Gln1111AsnfsX5 deletion variant was identified in 18 of 2684 proband chromosomes from individuals with breast or ovarian cancer (Blay 2013, Blesa 2000, Borg 2010, Durocher 1996, Jara 2006, Mahfoudh 2012, Torres 2006, Zhang 2011). The variant was also identified in dbSNP (ID: rs80357903) “With pathogenic allele”, HGMD, UMD (28X as a causal variant), and the BIC database (40X with clinical importance). One functional study found that the variant deregulated cell cycle progression and the expression of important regulators of cell motility and invasion (Yasmeen 2008). The p.Gln1111AsnfsX5 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1111 and leads to a premature stop codon 5 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs80357701; hg19: chr17-41244213;