chr17-43063330-TA-T

Variant names:

• chr17-43063330-TA-T
• rs273901751
• NM_007294.4:c.5193+2delT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5193+2delT variant causes a splice donor, intron 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, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 5.64
• Publications: 3 publications found

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]

BRCA1 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 55450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.5193+2delT		splice_donor intron	N/A	NP_009225.1
	BRCA1	NM_001407581.1		c.5259+2delT		splice_donor intron	N/A	NP_001394510.1
	BRCA1	NM_001407582.1		c.5259+2delT		splice_donor intron	N/A	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5193+2delT		splice_donor intron	N/A	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.5256+2delT		splice_donor intron	N/A	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.5193+2delT		splice_donor intron	N/A	ENSP00000419274.2

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33262

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104692

Other (OTH) AF: 0.0000166 AC: 1 AN: 60148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0225104), which strongly suggests a high chance of mosaicism in these individuals.

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

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2016

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 30, 1999

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Pathogenic:3

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 22505045; internal data). For these reasons, this variant has been classified as Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 14, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 08, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; 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

Apr 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
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

Other links and lift over

dbSNP: rs273901751; hg19: chr17-41215347;