17-43063374-CT-C

Position:

• chr17-43063374-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5153-2delA variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000685 in 1,458,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_acceptor, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 4.82

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0071530757 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4, offset of -48, new splice context is: ctctctatctccgtgaaaAGagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43063374-CT-C is Pathogenic according to our data. Variant chr17-43063374-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 55431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43063374-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5153-2delA		splice_acceptor_variant, intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5153-2delA		splice_acceptor_variant, intron_variant		1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458884 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726042

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 13, 2023	- -
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	New York Genome Center	Sep 09, 2022	The c.5153-2del variant (also known as 5272-2delA and IVS18-2delA) in BRCA1 has previously been reported in individuals with Hereditary breast and ovarian cancer (HBOC) [PMID: 11102986, 23110154, 28888541, 30787465] and it has been deposited in ClinVar [ClinVar ID: 55431] as Pathogenic for HBOC by multiple submitters. The c.5153-2del variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases.The c.5153-2del variant in BRCA1 is located in the canonical splice acceptor site of exon 18 of this 22-exon gene. It was demonstrated to result in skipping of exon 18, causing a frameshift and premature incorporation of termination codon (p.Trp1718SerfsTer1) [PMID: 12393792, 23239986]. Other variants affecting the same canonical splice acceptor site have also been reported in the literature in individuals with HBOC [PMID: 32596782]. Based on available evidence this inherited heterozygous c.5153-2del variant identified in BRCA1 is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 07, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 10, 2010	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Sep 16, 2024	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 27, 2017	The c.5153-2delA variant in BRCA1 has been identified 9 individuals with BCRA1-a ssociated cancers and segregated with disease in 4 affected relatives from 1 fam ily (Kiechle 2000; Breast Cancer Information Core (BIC) database). It was also a bsent from large population studies. This variant is a deletion of one nucleotid e in the invariant region (+/- 1,2) of the splice consensus sequence and is pred icted to cause altered splicing leading to an abnormal or absent protein. In sum mary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer (HBOC) in an autosomal dominant manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	This sequence change affects a splice site in intron 17 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer (PMID: 11102986, 12393792, 16528604, 23110154, 23239986, 25863477, 28888541). This variant is also known as 5272-2delA and IVS18-2delA. ClinVar contains an entry for this variant (Variation ID: 55431). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 12393792, 23239986, 24667779; Invitae). 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	Jul 22, 2021	Variant summary: BRCA1 c.5153-2delA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site which is also supported by a functional study (Wappenschmidt_2012). The variant was absent in 250880 control chromosomes (gnomAD). c.5153-2delA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (example: Judkins_2005, Grushko_2004, Kiechle_2002, Pern_2012, Perrin-Vidoz_2002, Wappenschmidt_2012, Rebbeck_2018) These data indicate that the variant is very likely to be associated with disease. Eight other ClinVar submitters (evaluation after 2018) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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	Color Diagnostics, LLC DBA Color Health	Nov 10, 2021	This variant deletes 1 nucleotide in intron 17 of the BRCA1 gene, disrupting the intron 17 splice acceptor site. This variant is also known as 5272-2delA in the literature. RNA studies have reported that this variant causes the out-of-frame skipping of exon 18, resulting in premature truncation (PMID: 12393792, 23110154). This variant has been reported in at least three individuals affected with breast cancer (PMID: 14760071, 23110154, 25863477, 33471991; Leiden Open Variation Database DB-ID BRCA1_004687) and additional families suspected of hereditary breast and ovarian cancer (PMID: 23239986). 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	Feb 09, 2022	The c.5153-2delA intronic pathogenic mutation results from the deletion of one nucleotide at position c.5153-2 and involves the canonical splice acceptor site before coding exon 17 in the BRCA1 gene. This mutation has been reported in multiple families of various ethnicities affected with breast and/or ovarian cancer (Kiechle et al. Hum Mutat. 2000 Dec;16(6):529-30; Sinilnikova OM et al. Fam Cancer. 2006;5(1):15-20; Kang E et al. Breast Cancer REs Treat. 2015 May;151(1):157-68; Rebbeck TR et al. Hum Mutat. 2018 05;39(5):593-620). Other studies have shown that this mutation leads to exon skipping resulting in a premature termination codon (Pern et al. PLoS One. 2012;7(10):e47993; Wappenschmidt et al. PLoS One. 2012;7(12):e50800; Perrin-Vidoz L et al. Hum Mol GEnet. 2002 Nov;11(23):2805-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this mutation is also designated as IVS18-2delA and 5272-2delA in published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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 25, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2022

Canonical splice site variant demonstrated to cause abnormal splicing resulting in a null allele in a gene for which loss-of-function is a known mechanism of disease (Perrin-Vidoz 2002, Wappenschmidt 2012); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Kiechle 2000, Sinilnikova 2006, Pern 2012, Kang 2015); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5272-2del or IVS18-2del; This variant is associated with the following publications: (PMID: 25863477, 23239986, 16528604, 20104584, 28888541, 12393792, 11102986, 23110154, 26187060, 16685647, 11802209, 17694537, 14760071, 16267036, 30787465) -

BRCA1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2024

The BRCA1 c.5153-2delA variant is predicted to result in a deletion affecting a canonical splice site. This variant has been reported in multiple individuals with breast cancer (Kiechle et al.. 2000. PubMed ID: 11102986; Pern et al., 2012. PubMed ID: 23110154). This variant has also been referred to as c.5272-2delA or IVS18-2delA in literature. RT-PCR analysis demonstrated that this variant cause exon 19 skipping, which is predicted to lead to a coding frameshift and premature protein truncation (Wappenschmidt et al., 2012. PubMed ID: 23239986). Multiple clinical labs have also interpreted this variant as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/55431/). This variant is interpreted 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

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: -12
DS_AL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs273901746; hg19: chr17-41215391;