rs80357579

Positions:

• chr17-43091759-CCT-C

Variant summary

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

The NM_007294.4(BRCA1):​c.3770_3771del​(p.Glu1257GlyfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,042 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:35
• Conservation: PhyloP100: 0.171

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 17-43091759-CCT-C is Pathogenic according to our data. Variant chr17-43091759-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 37546.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091759-CCT-C is described in Lovd as [Pathogenic]. Variant chr17-43091759-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3770_3771del	p.Glu1257GlyfsTer9	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.3770_3771del	p.Glu1257GlyfsTer9	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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: 0.00000796 AC: 2 AN: 251226 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135768

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461866 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727240

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:35

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:16

Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 08, 2018	The c.3770_3771delAG (p.Glu1257Glyfs*9) 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 7606717, 16683254, 17319787, 18627636, 23479189, 27553291). This variant has an extremely low frequency in large databases of genetic variation in the general population. Therefore, the c.3770_3771delAG (p.Glu1257Glyfs*9) variant in the BRCA1 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 19, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 01, 2023	A known pathogenic mutation was detected in the BRCA1 gene(p.Glu1257fs).his sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) 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 (rs80357993, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16683254, 17319787, 18627636, 23479189, 23683081). This variant is also known as 3890_3891delAG and 3889delAG. ClinVar contains an entry for this variant (Variation ID: 37546). For these reasons, this variant has been classified as Pathogenic. This variant was confirmed by Sanger sequencing. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 23, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 18, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
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	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	case-control	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	May 24, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1999	- -
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	Arcensus	Feb 01, 2013	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2022	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 individuals with a personal or family history consistent with pathogenic variants in this gene (Takahashi 1995, Liede 2002, Esteban Cardeosa 2010, Sakamoto 2016, Manchana 2019, Rashid 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3889_3890delAG; This variant is associated with the following publications: (PMID: 25802882, 16758124, 11597388, 28127413, 28477318, 30078507, 29922827, 28888541, 29884136, 33858029, 7606717, 12181777, 20033483, 26439132, 30350268, 32318955, 8807330, 11106241, 24289553, 26026974, 26757417, 19941167, 23317271, 17076205, 23683081, 21559243, 20960228, 26911350, 27983536, 27393621, 27836010, 26848529, 27553291, 29215753, 28176296, 29093764, 28152038, 27062684, 28528518, 29339979, 29752822, 29907814, 29470806, 28724667, 28993434, 30675318, 30702160, 30720863, 30720243, 30972954, 23479189, 31815095, 31528241, 31957001, 31447099, 31589614, 32341426, 31825140, 32885271, 33151324, 31742824, 34645131, 35377489) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 21, 2021	The BRCA1 c.3770_3771del (p.Glu1257Glyfs*9) 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 with breast or ovarian cancer (PMID: 23479189 (2013), 30972954 (2019), 31957001 (2020); BRCA Exchange (http://brcaexchange.org/)). The frequency of this variant in the general population, 0.000087 (1/11484 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	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Glu1257Glyfs*9 variant was identified in 27 of 18350 proband chromosomes (frequency: 0.0015) from individuals or families with breast or ovarian cancer (Blay 2013, Chen 2009, Cock-Rada 2018, de Juan Jimenez 2013, Heramb 2018, Hirotsu 2014, Konecny 2007, Thirthagiri 2008, van der Hout 2006). The variant was also identified in the following databases: dbSNP (ID: rs80357993) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and fourteen other submitters), COGR, LOVD 3.0 (28x), UMD-LSDB (25x causal), BIC Database (23x with clinical importance), ARUP Laboratories (definitely pathogenic), and in Zhejiang University database (2x). The variant was not identified in Cosmic or MutDB databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3770_3771del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1257 and leads to a premature stop codon at position 1265. 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 14, 2024	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 29, 2023	Variant summary: BRCA1 c.3770_3771delAG (p.Glu1257GlyfsX9) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251226 control chromosomes (gnomAD). c.3770_3771delAG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Takahashi_1995, Judkins_2005, Hansa_2012, Thirthagiri_2008, Sun_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 18627636, 7606717, 23317271, 28724667). 21 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Cancer Genomics Lab, PINUM Cancer Hospital	May 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) 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 (rs80357993, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16683254, 17319787, 18627636, 23479189, 23683081). This variant is also known as 3890_3891delAG and 3889delAG. ClinVar contains an entry for this variant (Variation ID: 37546). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2021	The c.3770_3771delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3770 to 3771, causing a translational frameshift with a predicted alternate stop codon (p.E1257Gfs*9). This mutation has been reported in multiple breast and ovarian cancer families to date (Couch FJ et al. Hum. Mutat., 1996;8:8-18; Liede A et al. Am. J. Hum. Genet., 2002 Sep;71:595-606; Blay P et al. BMC Cancer, 2013 May;13:243; Rashid MU et al. BMC Cancer, 2016 08;16:673; Shi T et al. Int J Cancer, 2017 05;140:2051-2059; Cock-Rada AM et al. Fam Cancer, 2018 01;17:23-30; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Wen WX et al. J Med Genet, 2018 02;55:97-103; Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27; Li JY et al. Int J Cancer, 2019 01;144:281-289; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Meng H et al. Int J Cancer, 2020 06;146:3044-3052; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Dorling et al. N Engl J Med. 2021 02;384:428-439; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Feng Z et al. Ann Transl Med, 2021 Mar;9:364). Of note, this alteration is also designated as 3889delAG 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	Nov 21, 2022	This variant deletes 2 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 also known as 3889delAG and 3888delGA in the literature according to the BIC nomenclature. This variant has been reported in over thirty individuals affected with breast and/or ovarian cancer (PMID: 18627636, 23479189, 23683081, 26026974, 26757417, 26824983, 27553291, 28176296, 28528518, 29339979). This variant has been identified in 2/251226 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. -

Carcinoma of pancreas Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Mar 04, 2021

- -

Ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

Jun 27, 2017

- -

BRCA1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The BRCA1 c.3770_3771delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu1257Glyfs*9). This variant has been reported in patients with early onset and familial breast and ovarian cancer (de Juan Jiménez et al. 2013. PubMed ID: 23479189; Gabaldó Barrios. 2017. PubMed ID: 28477318). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37546/). Frameshift variants in BRCA1 are expected to be pathogenic. We interpret this variant as pathogenic. -

Ovarian neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 09, 2021

- -

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: rs80357579; hg19: chr17-41243776;