rs758780152

Positions:

chr17-43047728-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007294.4(BRCA1):c.5407-25T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 2.00

Variant links:

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 links:

BRCA1 (HGNC:):

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.5407-25T>A		intron_variant		ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.5407-25T>A		intron_variant		1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251402

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461098

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726914

show subpopulations

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2023	Variant summary: BRCA1 c.5407-25T>A is located at a position not widely known to affect splicing. While splice predictors via Alamut do not predict a significant impact on splicing, a different tool, SpliceAI, does predict the loss of cannonical splice acceptor. Sequencing of patient-derived cDNA from blood, normal breast and ovarian tissue showed the variant to lead to skipping of exon 23, resulting in a frameshift and protein truncation (p.Gly1803GlnfsTer11) (Hoberg-Vetti_2020). Additionally, Western blot analysis of transiently expressed BRCA1 proteins showed a reduced amount of truncated protein compared to wild-type, however a small amount of full-length transcript was generated from the c.5407-25T>A allele (Hoberg-Vetti_2020). The variant allele was found at a frequency of 4e-06 in 251402 control chromosomes. c.5407-25T>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Hoberg-Vetti_2016, Hoberg-Vetti_2020, Alenezi_2022, Konstantopoulou_2014). In one publication, the variant was reported in sisters with bilateral high-grade serous ovarian carcinoma and sequencing of the tumor DNA from these variant carriers showed complete loss of the wild-type allele (Alenezi_2022). Additionally, an analysis of 20 apparently unrelated families carrying the variant showed 23/49 female carriers (46.9%) were affected by either breast or ovarian cancer with a mean age of 49.9 years while 26 unaffected female carriers included 7 women who were 50 years or older without having undergone prophylactic surgery. The authors state that their results indicate the variant is a likely pathogenic variant with reduced penetrance, possibly related to the small "leakage" of normal transcript from this splice variant. Due to the lower median age at cancer diagnosis between this variant and other frameshift variants, as well as the family histories of these patients being compatible with lower penetrance, the authors suggest the magnitude of risk may be lower for this variant compared to truncating BRCA1 variants. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, three classified the variant as likely pathogenic while one classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 25, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the BRCT domain, which is important for DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). While functional studies have not been performed to directly test the effect of this variant on BRCA1 protein function, this suggests that disruption of this region of the protein is causative of disease. Studies have shown that this variant results in skipping of exon 22 and introduces a new termination codon (PMID: 26350514, 32203205; Invitae; external communication). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 371817). This variant is also known as IVS22-25T>A. This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12774040, 24010542, 26350514, 29339979, 35456503). This variant is present in population databases (rs758780152, gnomAD 0.002%). This sequence change falls in intron 21 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 19, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2023	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2024

Non-canonical splice variant demonstrating aberrant splicing (PMID: 26350514, 31992191); Observed in individuals with personal and/or family history of breast and/or ovarian cancer and reported as a recurrent variant in the Norwegian population (PMID: 12774040, 24010542, 26350514, 29339979, 30678073, 35456503); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS22-25T>A; This variant is associated with the following publications: (PMID: 28726806, 26350514, 12774040, 29339979, 24010542, 30678073, 27974384, 30209399, 32623769, 35456503, 34981296, 31992191, 32203205) -

BRCA1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2024

The BRCA1 c.5407-25T>A variant is predicted to interfere with splicing. This variant has been reported in over 20 families with a history of hereditary breast and/or ovarian cancer (Figure 1, Alenezi et al. 2022. PubMed ID: 35456503; Table 2, Høberg-Vetti et al. 2020. PubMed ID: 32203205; Table 2, Heramb et al. 2018. PubMed ID: 29339979; Table 2, Høberg-Vetti et al. 2016. PubMed ID: 26350514; Table 2, Hamann et al. 2003. PubMed ID: 12774040). This variant has also been reported in an individual with ovarian cancer, and tumor DNA profiling identified loss of heterozygosity that resulted in wild-type allele dropout and retention of the c.5407-25T>A allele (Alenezi et al. 2022. PubMed ID: 35456503). Analysis of patient-derived cDNA from blood, normal breast and ovarian tissue indicates that this variant leads to skipping of exon 23, resulting in frameshift and protein truncation, p.Gly1803GlnfsTer11 (Høberg-Vetti et al. 2020. PubMed ID: 32203205). In vitro experimental studies suggest this variant results in reduced protein expression compared to wildtype (Høberg-Vetti et al. 2020. PubMed ID: 32203205). This variant is reported in 2 of ~283,000 alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations of uncertain significance and likely pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/371817/). This variant is interpreted as likely pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2024

The c.5407-25T>A intronic variant results from a T to A substitution 25 nucleotides upstream from coding exon 21 in the BRCA1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Høberg-Vetti H et al. Eur. J. Hum. Genet., 2016 06;24:881-8; Høberg-Vetti H et al. Eur J Hum Genet . 2020 08;28(8):1078-1086). This alteration has been identified in several patients with a personal or family history of breast and/or ovarian cancer (Hamann U et al. Eur J Hum Genet, 2003 Jun;11:464-7; Konstantopoulou I et al. Clin Genet, 2014 Jan;85:36-42; Høberg-Vetti H et al. Eur J Hum Genet, 2016 06;24:881-8; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Alenezi WM et al. Genes (Basel), 2022 Apr;13:). One publication reports that this variant may have reduced penetrance based on clinical data from 20 families with the variant, although no details on co-segregation or clinical phenotypes were reported (Høberg-Vetti H et al. Eur J Hum Genet . 2020 08;28(8):1078-1086). Of note, this alteration is also referred to as IVS22-25A>T in the literature. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

research

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

Jan 31, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.095

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.41

Position offset: -25

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over