17-43099773-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_007294.4(BRCA1):c.547+2T>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: not found (cov: 31)

Consequence

BRCA1
NM_007294.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:18

Conservation

PhyloP100: 3.92

Publications

16 publications found

Variant links:

COSMIC-nc: COSV58804428

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

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 17-43099773-A-T is Pathogenic according to our data. Variant chr17-43099773-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37674.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.547+2T>A		splice_donor_variant, intron_variant	Intron 7 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.547+2T>A		splice_donor_variant, intron_variant	Intron 7 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:8

May 11, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 01, 2022

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRCA1:c.547+2T>A variant is classified as PATHOGENIC (ENIGMA criteria 2017) BRCA1:c.547+2T>A is a single nucleotide substitution in intron 8 at +2 bases from the last nucleotide of exon 8. BRCA1:c.547+2T>A is also described as IVS8+2T>A in the scientific literature using legacy nomenclature. This variant is predicted to effect aberrant splicing. Functional studies confirm BRCA1:c.547+2T>A results in skipping of exon 8 generating a frameshift transcript (BRCA1:r.442_547) that encodes premature termination of the protein synthesis (BRCA1:p.Gln148AspfsTer51) (Houdayer et al., 2012, PMID:22505045, Colombo et al., 2013, PMID:23451180). This variant has been reviewed by the ENIGMA expert review panel: ENIGMA determine BRCA1:c.547+2T>A as consistent with an IARC Class 5 variant equivalent to ACMG classification of Pathogenic. BRCA1:c.547+2T>A (rs80358047) is absent from population databases and is not on record in FLOSSIES. BRCA1:c.547+2T>A has been reported in multiple unrelated individuals with breast or ovarian cancer (Marchetti et al., 2018, PMID:30128899, Shattuck-Eidens et al., 1997 PMID:9333265, Trujillano et al., 2015 PMID:25556971). BRCA1:c.547+2T>A is on record in ClinVar (Variation ID:37674) reported by multiple clinical laboratories without conflict as pathogenic in association with Hereditary breast and ovarian cancer syndrome. This variant is listed in HGMD as ‘disease causing mutation’ in association with breast and/or ovarian cancer (Accession:CS973719).

Nov 27, 2017

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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

Feb 10, 2022

MGZ Medical Genetics Center

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

Apr 03, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.442_547del transcript (encoding predicted non-functional protein).

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Hereditary breast ovarian cancer syndrome

Pathogenic:4

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 7 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 breast and/or ovarian cancer (PMID: 9333265, 23940062, 25556971). This variant is also known as IVS8+2T>A. ClinVar contains an entry for this variant (Variation ID: 37674). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24667779). For these reasons, this variant has been classified as Pathogenic.

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

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

May 05, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA1 c.547+2T>A 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of BRCA1 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Steffensen_2014). The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.547+2T>A has been observed in individual(s) affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Shattuck-Eidens_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9333265, 24667779). ClinVar contains an entry for this variant (Variation ID: 37674). Based on the evidence outlined above, the variant was classified as pathogenic.

Hereditary cancer-predisposing syndrome

Pathogenic:3

Feb 28, 2022

Sema4, Sema4

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

Sep 14, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.547+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 6 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been detected in numerous patients and families affected with breast and/or ovarian cancer (Pyne MT et al. Mutat. Res. 1999 Aug;406:101-7; Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108; Tedaldi G et al. Oncotarget 2017 Jul;8:47064-47075; Marchetti C et al. Ann. Surg. Oncol. 2018 Nov;25(12):3701-3708; Cotrim DP et al. BMC Cancer. 2019 Jan;19(1):4). RNA studies have demonstrated that this alteration causes coding exon 6 skipping (total exon 8 in the literature), which results in a transcript that is subject to nonsense-mediated mRNA decay (Ambry internal data; Pyne MT et al. Mutat. Res. 1999 Aug;406:101-7; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Colombo M et al. PLoS ONE 2013 Feb;8:e57173). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Feb 10, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes a T to A nucleotide substitution at the +2 position of intron 7 of the BRCA1 gene. RNA studies have reported that the variant causes the out-of-frame skipping of exon 7, resulting in premature termination, in RNA derived from carriers and in a minigene splicing assay (PMID: 10479726, 22505045, 23451180, 24667779). This variant has been detected in at least seven individuals affected with breast or ovarian cancer (PMID: 10479726, 25452441, 27328445, 28423363, 30128899, 30606148; Color internal data). 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.

not provided

Pathogenic:2

Mar 28, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant disrupts a canonical splice-donor site and interferes with normal BRCA1 mRNA splicing. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 23940062 (2013), 25452441 (2015), 25556971 (2015)) and ovarian cancer (PMID: 30606148 (2019), 25556971 (2015)). Published functional studies show that this variant causes aberrant mRNA splicing that result in skipping of exon 8 (PMID: 10479726 (1999), 22505045 (2012), 23451180 (2013), 24667779 (2014)). Based on the available information, this variant is classified as pathogenic.

Aug 03, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant resulting in a null allele in a gene for which loss-of-function is a known mechanism of disease (Houdayer 2012, Colombo 2013, Steffensen 2014); Observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Shattuck-Eidens 1997, Turner 1999, Smith 2000, Grushko 2004, Johnston 2012, Colombo 2013); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as c.666+2T>A or IVS8+2T>A; This variant is associated with the following publications: (PMID: 23940062, 9333265, 25556971, 23451180, 28423363, 27328445, 29346284, 30606148, 22703879, 26046366, 25525159, 22505045, 10479726, 24667779, 14760071, 10506595, 17284709, 11121624, 27600092, 29446198, 33287145)

Breast and/or ovarian cancer

Pathogenic:1

Feb 23, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

MetaRNN

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

3.9

PROVEAN

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.0

GERP RS

5.2

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: 2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over