rs80357678

chr17-43091613-CAA-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.3916_3917del(p.Leu1306AspfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L1306L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 1.31

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43091613-CAA-C is Pathogenic according to our data. Variant chr17-43091613-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 55049.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091613-CAA-C is described in Lovd as [Pathogenic]. Variant chr17-43091613-CAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3916_3917del	p.Leu1306AspfsTer23	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3916_3917del	p.Leu1306AspfsTer23	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5

Likely pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Nov 02, 2016	This variant has previously been described as disease-causing for breast-ovarian cancer by De Benedetti et al. in 1996 and Zuradelli et al. in 2010 (HGMD professional 2015.3-PMID: 8808710 and 20373018). This variant has not been described by the Exome Sequencing Project, 1000 genome and ExAC. This variant has not been previously detected by CentoMD. However, this variant is been reported in two clinical entries in ClinVar as pathogenic. The patient presented with right breast cancer at 17 years of age, later she was detected with ovarian cancer at the age of 49 years which had metastasized to liver, peritoneum and brain. She passed away at the age of 56 years. Her two daughters of age 30 years and 26 years were also diagnosed to be heterozygous for the same mutation. -
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	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 03, 2012	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Leu1306Aspfs*23) 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 a BRCA1-related disease (PMID: 8808710, 20373018, 25452441, 26187060). This variant is also known as 4035delTT (L1306fs). ClinVar contains an entry for this variant (Variation ID: 55049). 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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 22, 2021	This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4035delTT based on the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 11044645, 15340362, 20373018, 21614564, 25452441). 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	Apr 30, 2021	The c.3916_3917delTT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3916 to 3917, causing a translational frameshift with a predicted alternate stop codon (p.L1306Dfs*23). This mutation has been reported in multiple patients with hereditary breast and ovarian cancer (HBOC) (De Benedetti VM et al. Oncogene, 1996 Sep;13:1353-7; Zhang J et al. Breast Cancer Res Treat, 2012 Apr;132:421-8; Cao W et al. Anat Rec (Hoboken), 2013 Feb;296:273-8; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Kwong A et al. J Med Genet, 2016 Jan;53:15-23; Kim YC et al. Oncotarget, 2016 Feb;7:9600-12; Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Shi T et al. Int J Cancer, 2017 05;140:2051-2059; Zhao Q et al. J Gynecol Oncol, 2017 Jul;28:e39; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Palmero EI et al. Sci Rep, 2018 06;8:9188; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Wang X et al. Mol Genet Genomic Med, 2019 06;7:e677; Concolino P et al. Int J Mol Sci, 2019 Jul;20; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Santonocito C et al. Cancers (Basel), 2020 May;12). This mutation has also been reported in patients with pancreatic cancer (Toss A et al. Cancers (Basel), 2019 Feb;11). This mutation has been reported to co-occur with mutations in BRCA2 (Zuradelli M et al. Breast Cancer Res. Treat. 2010 Nov;124:251-8; Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18:112). 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. -

Ovarian 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

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Oct 04, 2019

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs80357678; hg19: chr17-41243630;