rs273901751

Positions:

• chr17-43063330-TA-T

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.5193+2del variant causes a splice donor change. The variant allele was found at a frequency of 0.00000206 in 1,453,728 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: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_donor
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 5.64

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43063330-TA-T is Pathogenic according to our data. Variant chr17-43063330-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 55450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43063330-TA-T is described in Lovd as [Pathogenic]. Variant chr17-43063330-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5193+2del		splice_donor_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5193+2del		splice_donor_variant		1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453728 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 723860

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: 0.00000181

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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)	Dec 30, 1999	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Mar 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	This sequence change affects a splice site in intron 18 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 BRCA1-related conditions (PMID: 7493024, 10644434, 12759930, 24549055). This variant is also known as 5312+2delT and IVS19+2delT. ClinVar contains an entry for this variant (Variation ID: 55450). Studies have shown that disruption of this splice site results in skipping of exon 18 and introduces a premature termination codon (PMID: 22505045; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The c.5193+2delT variant in BRCA1 has been reported in at least 7 families with hereditary breast and/or ovarian cancer (HBOC) and segregated with disease in at least 3 affected individuals from 1 family (Wagner 1999, Claes 2003, Gayther 1995, BIC database). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 55450). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies on patient cells show that this variant leads to exon 19 skipping, leading to a premature stop codon (Houdayer 2012, Claes 2003). This is expected to lead to a truncated or absent protein and loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant HBOC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS3_Moderate, PS4_Moderate, PP1. -
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	Mar 14, 2022	This variant causes a deletion of one nucleotide in intron 18 of the BRCA1 gene. This variant is also known as IVS19+2delT based on Breast Cancer Information Core (BIC) nomenclature, and has also been referenced as 5312+2delT in the literature. RNA studies have shown that this variant produces two mutant transcripts (PMID: 12759930, 22505045). One mutant transcript causes an in-frame skipping of exon 19, creating a partial deletion of 13 amino acid residues from the BRCT1 domain. The other mutant transcript causes an out-of-frame skipping of exons 18 and 19, creating a premature translation stop signal that 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: 7493024, 10644434, 12759930, 24549055, 33302456). 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	Sep 23, 2021	The c.5193+2delT intronic pathogenic mutation results from a deletion of one nucleotide at the +2 position downstream of coding exon 17 of the BRCA1 gene. Also designated as IVS19+2delT in published literature, this alteration has been previously identified in hereditary breast and/or ovarian cancer cohorts (Gayther SA et al. Nat. Genet. 1995 Dec;11(4):428-33; Wagner T et al. Genomics 1999 Dec; 62(3):369-76; Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22(11):1305-13). Splicing assays from lymphoblastoid cell lines of carriers indicate that this alteration results in coding exon 17 skipping and removes 13 amino acids from the BRCT domain (Houdayer C et al. Hum. Mutat. 2012 Aug;33(8):1228-38; Claes K et al. Genes Chromosomes Cancer 2003 Jul;37(3):314-20). 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 weaken the native splice donor site. 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 classified as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2022

Canonical splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease (Claes 2003, Houdayer 2012); Observed in individuals with a personal and/or family history consistent with pathogenic variants in this gene (Gayther 1995, Wagner 1999, Claes 2003, Castera 2014, Lovejoy 2020); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5312+2del or IVS19+2del; This variant is associated with the following publications: (PMID: 10644434, 20104584, 12759930, 22505045, 33087929, 7493024, 24549055, 33302456) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs273901751; hg19: chr17-41215347;