rs80357887

chr17-43099850-TAG-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.470_471del(p.Ser157Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:19 O:1
• Conservation: PhyloP100: 1.23

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 17-43099850-TAG-T is Pathogenic according to our data. Variant chr17-43099850-TAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 37608.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43099850-TAG-T is described in Lovd as [Pathogenic]. Variant chr17-43099850-TAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.470_471del	p.Ser157Ter	frameshift_variant	7/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.470_471del	p.Ser157Ter	frameshift_variant	7/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7 Other:1

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, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Apr 10, 2022	The c.470_471del;p.(Ser157*) variant creates a premature translational stop signal in the BRCA1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 37608; PMID: 11149413; PMID: 22970155; PMID: 23683081; PMID: 29907814) - PS4. This variant is not present in population databases (rs80357887- 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	Baylor Genetics	May 17, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 27, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 29, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PP1 moderated -
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. -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2020	Variant summary: BRCA1 c.470_471delCT (p.Ser157X) 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. The variant was absent in 251450 control chromosomes. c.470_471delCT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (delaHoya_2002, Judkins_2005, Kwong_2012, Peixoto_2014). These data indicate that the variant is very likely to be associated with disease. Eight 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	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	This sequence change creates a premature translational stop signal (p.Ser157*) 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 breast and ovarian cancer (PMID: 11149413, 22970155, 23683081, 24916970). This variant is also known as 589delCT. ClinVar contains an entry for this variant (Variation ID: 37608). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 19, 2022	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/families with suspected hereditary breast/ovarian cancer syndrome in the published literature (PMIDs: 30702160 (2019), 29907814 (2018), 29752822 (2018), 29446198 (2018), 29176636 (2018), 24916970 (2015), 23683081 (2013), 22970155 (2012), 22762150 (2012), 18627636 (2008), 11149413 (2001), and 10340909 (1999)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 15, 2022	The BRCA1 c.470_471delCT; p.Ser157Ter variant (rs80357887), also known as 589delCT, is reported in several individuals and families with hereditary breast and/or ovarian cancer (de la Hoya 2001, de lay Hoya 2002, Fernandes 2016, Wen 2018). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37608) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes two nucleotides, leading to an immediate nonsense codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is classified as pathogenic. References: de la Hoya M et al. Spanish family study on hereditary breast and/or ovarian cancer: analysis of the BRCA1 gene. Int J Cancer. 2001 Jan 1;91(1):137-40. PMID: 11149413. de la Hoya M et al. Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing. Int J Cancer. 2002 Feb 1;97(4):466-71. PMID: 11802208. Fernandes GC et al. Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. Oncotarget. 2016 Dec 6;7(49):80465-80481. PMID: 27741520. Wen WX et al. Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. J Med Genet. 2018 Feb;55(2):97-103. PMID: 28993434. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2021	Nonsense 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 (Tang 1999, de la Hoya 2001, Kwong 2012, Blay 2013, Peixoto 2015); Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 589_590delCT; This variant is associated with the following publications: (PMID: 17603881, 24249303, 11149413, 22970155, 26187060, 24916970, 28127413, 24578176, 27157322, 12955716, 23199084, 23683081, 18627636, 10340909, 27553291, 28961279, 11802208, 29752822, 28993434, 30702160, 27741520, 29176636, 31825140, 30787465, 32101877) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 25, 2022	The c.470_471delCT pathogenic mutation, located in coding exon 6 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 470 to 471, causing a translational frameshift with a predicted alternate stop codon (p.S157*). This alteration has been identified as a recurrent mutation in both Spanish and Southern Chinese breast and/or ovarian cancer cohorts (de la Hoya M et al. Int. J. Cancer 2001 Jan;91:137-40; Díez O et al. Hum. Mutat. 2003 Oct;22:301-12; Kwong A et al. PLoS ONE 2012 Sep;7:e43994). This mutation has also been reported in multiple international HBOC cohorts (Pinto P et al. Breast Cancer Res. Treat. 2016 Sep;159:245-56; Fernandes GC et al. Oncotarget 2016 Oct;7(49):80465-80481; Bhaskaran SP et al. Int. J. Cancer 2019 Jan; Arai M et al. J. Hum. Genet. 2018 Apr;63:447-457; Palmero EI et al. Sci Rep. 2018 Jun;8:9188; Wen WX et al. J. Med. Genet. 2018 Feb;55:97-103; Li JY et al. Int. J. Cancer 2019 01;144:281-289; Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration is also designated as 589_590delCT 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	May 19, 2021	This variant deletes 2 nucleotides in exon 7 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 589delCT and 589_590delCT in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in over 10 individuals affected with breast and ovarian cancer (PMID: 11802208, 12955716, 16998791, 20617377, 22970155, 27553368, 27741520, 29752822) and in suspected hereditary breast and ovarian cancer families (PMID: 23683081, 24249303, 24916970). 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. -

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

May 13, 2022

- -

Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

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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: rs80357887; hg19: chr17-41251867;