chr17-43045792-CTGCCCAAT-C

Position:

• chr17-43045792-CTGCCCAAT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5470_5477del​(p.Ile1824AspfsTer3) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 frameshift, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 3.73

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 47 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43045792-CTGCCCAAT-C is Pathogenic according to our data. Variant chr17-43045792-CTGCCCAAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 55591.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43045792-CTGCCCAAT-C is described in Lovd as [Pathogenic]. Variant chr17-43045792-CTGCCCAAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5470_5477del	p.Ile1824AspfsTer3	frameshift_variant, splice_region_variant	23/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5470_5477del	p.Ile1824AspfsTer3	frameshift_variant, splice_region_variant	23/23	1	NM_007294.4	ENSP00000350283	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:11

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4

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	Baylor Genetics	Jan 01, 2024	- -
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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 20, 2002	- -

Breast neoplasm Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	Nov 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3DMed Clinical Laboratory Inc	Nov 20, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 12, 2021	This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been identified in individuals with breast cancer and/or ovarian cancer, as well as in a healthy control in the published literature (PMIDs: 28294317 (2017), 27257965 (2016), 26852015 (2016), 26824983 (2016), 25863477 (2015), 25366075 (2014), 18512148 (2009), 17922413 (2007), 17851763 (2008), 17680524 (2007), 16515586 (2006), 16455195 (2007), and 15117986 (2004)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2016	This deletion of eight nucleotides in BRCA1 is denoted c.5470_5477delATTGGGCA at the cDNA level and p.Ile1824AspfsX3 (I1824DfsX3) at the protein level. The normal sequence, with the bases that are deleted in braces, is AGCA[ATTGGGCA]GATG. The deletion causes a frameshift, which changes an Isoleucine to an Aspartic Acid at codon 1824, and creates a premature stop codon at position 3 of the new reading frame. Even though this frameshift occurs in the last exon of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 40 amino acids are no longer translated, disrupting the BRCT2 domain. This variant is predicted to cause loss of normal protein function through protein truncation. Also reported as BRCA1 5589del8 or 5589_5596delATTGGGCA using alternate nomenclature, this variant has been reported in individuals with a personal and/or family history of early-onset breast and/or ovarian cancer and is a recurrent pathogenic variant in the Chinese population (Choi 2004, Ahn 2007, Hu 2007, Li 2008, Kim 2014, Cao 2016). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 02, 2021	This variant deletes 8 nucleotides in exon 23 of the BRCA1 gene, creating a premature translation stop signal in the last coding exon. While this variant is not expected to trigger nonsense-mediated decay, the truncation is predicted to delete the C-terminus of the BRCT domain that is important for phosphopeptide binding and DNA damage response (PMID: 25701377). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in numerous individuals affected with hereditary breast and ovarian cancer in the literature and is a highly recurrent mutation in the Chinese population (PMID: 15117986, 16455195, 17680524, 17851763, 22798144, 25366075, 25863477, 26824983, 26848529, 26852015, 27257965, 27393621, 28294317, 29487695, 29752822, 29805665, 30982232, 31054147, 31174498). 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	Ambry Genetics	Dec 17, 2023	The c.5470_5477delATTGGGCA pathogenic mutation, located in coding exon 22 of the BRCA1 gene, results from a deletion of 8 nucleotides at positions 5470 to 5477, causing a translational frameshift with a predicted alternate stop codon (p.I1824Dfs*3). This mutation (also sometimes designated as 5589del8 in the literature) is recurrent in the Chinese population and has also been identified in Korean breast/ovarian cohorts (Choi D et al. J Clin Oncol. 2004 May 1;22(9):1638-45; Hu Z et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2007 Aug;24(4):378-81; Chen W et al. Breast Cancer Res. Treat. 2009 Sep; 117(1):55-60; Ahn SH et al. Cancer Lett. 2007 Jan; 245(1-2):90-5; Kim H et al. Breast Cancer Res. Treat. 2012 Aug; 134(3):1315-26; Li WF et al. Breast Cancer Res. Treat. 2008 Jul; 110(1):99-109; Meng H et al. Int J Cancer. 2020 06;146:3044-3052; Wu Y et al. Hereditas. 2020 Dec;157:1; Zeng C et al. Breast Cancer Res Treat. 2020 Jun;181:465-473). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This alteration occurs at the 3' terminus of the BRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 2% of the protein. However, premature stop codons are typically deleterious in nature, and the impacted region is critical for protein function (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

This sequence change creates a premature translational stop signal (p.Ile1824Aspfs*3) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the BRCA1 protein. 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/or ovarian cancer (PMID: 15117986, 16455195, 25366075, 25863477, 26824983, 26848529, 26852015, 27257965). This variant is also known as 5589del8. ClinVar contains an entry for this variant (Variation ID: 55591). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Arg1835*) have been determined to be pathogenic (PMID: 8554067, 16683254, 24504028). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80357973; hg19: chr17-41197809;