17-43082403-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_007294.4(BRCA1):c.4357+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000186 in 1,613,594 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:24

Conservation

PhyloP100: 3.70

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 17-43082403-C-T is Pathogenic according to our data. Variant chr17-43082403-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37584.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43082403-C-T is described in Lovd as [Pathogenic]. Variant chr17-43082403-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.4357+1G>A		splice_donor_variant, intron_variant	Intron 12 of 22	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.4357+1G>A		splice_donor_variant, intron_variant	Intron 12 of 22	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251154

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135750

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:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461320

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:11

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2014

Pathway Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2016

Counsyl

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

- -

Aug 10, 2015

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.9999 -

Oct 18, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 11, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.4357+1G>A variant results in a substitution at the consensus splice donor site. A functional study conducted in patient cells demonstrated that this variant results in abnormal splicing which is predicted to result in a frameshift and premature termination of translation, leading to nonsense mediated mRNA decay (PMID: 21769658). Across a selection of the available literature, this variant has been identified in more than ten individuals with breast or ovarian cancer, including 5% of African American patients in a multi-center cohort (PMID: 21769658; PMID: 27425403; PMID: 29446198; PMID: 30322717; PMID: 31825140). This variant has also been detected in an individual with prostate cancer (PMID: 29368341). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000046 in the European (Finnish) population This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.4357+1G>A variant has been classified as pathogenic for hereditary breast and ovarian cancer. -

Mar 07, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c. 4357+1G>A (also known as IVS13+1G>A) variant in the BRCA1 gene has been reported in multiple patients with breast cancer from two families breast cancer patients (PMID15533909, PMID21769658). In the first family, The first patientthe proband was diagnosed at 30 years of age and with three female relatives of the proband were diagnosed with breast cancer before age 40 (PMID 5533909). The second patient in the second family was diagnosed at 26 years of age without with no known family history (PMID21769658). In silico analysis and experimental studies suggest that this variant causes exon 13 skipping (PMID24667779,21735045, 21769658). A multifactorial likelihood algorithm also predicts this variant to be deleterious (PMID 17924331). Based on the current evidence, this c. 4357+1G>A variant in the BRCA1 gene is classified as pathogenic. -

not provided

Pathogenic:5

Jun 01, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -

Sep 06, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to result skipping of exon 12 which is predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Thomassen 2012, Steffensen 2014); Observed in individuals with BRCA1-related cancers (Pal 2004, Thomassen 2012, Couch 2015, Pal 2015, Alemar 2016, Frey 2017, Delgado-Balderas 2018, Isaacsson Velho 2018); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Easton 2007, Lindor 2012); Classified as pathogenic by a well-established clinical consortium and/or database (ClinVar); Also known as 4476+1G>A (IVS13+1G>A); This variant is associated with the following publications: (PMID: 17924331, 30787465, 21735045, 15533909, 26287763, 24013928, 24797986, 20838878, 19241424, 25920394, 27425403, 25085752, 25525159, 28495237, 28476184, 25452441, 20104584, 26295337, 29368341, 28918466, 29997359, 26681312, 29907814, 30702160, 29446198, 30720243, 30322717, 21769658, 24667779, 33646313, 31447099, 31825140, 21990134) -

Oct 11, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.4357+1G>A variant (rs80358027), also known as IVS13+1G>A, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Alemar 2016, Carter 2018, Pal 2004, Thomassen 2012). This variant is found on a single chromosome in the Genome Aggregation Database (1/251154 alleles), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 13, which is likely to disrupt gene function. Consistent with this, RNA analyses from a patient carrying this variant demonstrate skipping of exon 13, leading to a frameshift (Thomassen 2012). Based on available information, this variant is considered to be pathogenic. References: Alemar B et al. Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations. Cancer Genet. 2016 Sep;209(9):417-422. PMID: 27425403. Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Pal T et al. BRCA1 and BRCA2 mutations in a study of African American breast cancer patients. Cancer Epidemiol Biomarkers Prev. 2004 Nov;13(11 Pt 1):1794-9. PMID: 15533909. Thomassen M et al. Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members. Breast Cancer Res Treat. 2012 Apr;132(3):1009-23. PMID: 21769658. -

Hereditary breast ovarian cancer syndrome

Pathogenic:4

Apr 27, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA1 c.4357+1G>A variant involves the alteration of a conserved intronic nucleotide located at the canonical splicing site. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant abolishes the 5' splicing donor site. These predictions have been confirmed by RT-PCR showing that it leads to skipping of exon 12 (legacy exon 13) and frameshift p.Arg1397TyrfsX2 (Thomassen_2011). This variant was found in 1/121252 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It has also been reported in multiple HBOC patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Nov 27, 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 12 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 present in population databases (rs80358027, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 15533909, 20104584, 24013928, 24797986, 25085752, 25452441, 26681312). This variant is also known as IVS13+1G>A. ClinVar contains an entry for this variant (Variation ID: 37584). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21735045, 21769658, 24667779; internal data). 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

- -

Aug 10, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4357+1G>A variant (also known IVS13+1G>A) in BRCA1 has been reported in >30 individuals with breast, ovarian or other associated cancers and segregated with disease in 3 affected individuals from 1 family (Pal 2004 PMID: 15533909, Couch 2015 PMID:25452441, Susswein 2016 PMID: 26681312, Tihomirova 2014 PMID: 24797986, Thomassen 2012 PMID: 21769658, Isaacsson 2018 PMID: 29368341, Alemar 2016 PMID: 27425403, Carter 2018 PMID: 30322717, Akbari 2014 PMID:23458327). It has also been identified in 0.005% (1/21620) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on August 10, 2015 by the ClinGen-approved Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel (Variation ID 37584). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal autosomal dominant HBOC. Multifactorial likelihood algorithm using genetic, in silico, and statistical data determined to have a high probability of being pathogenic (Easton 2007 PMID: 17924331, Lindor 2012 PMID: 21990134, Pruss 2014 PMID: 25085752). Experimental studies have shown that this variant causes exon 12 skipping in BRCA1 (Steffensen 2014 PMID: 24667779, Thomassen 2012 PMID: 21769658). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PVS1_Strong, PM2, PM5, PS3_Supporting. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Jun 13, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to A nucleotide substitution at the +1 position of intron 12 of the BRCA1 gene. RNA studies have reported this variant to cause the out-of-frame skipping of exon 12 in carrier RNA and in minigene splicing assay (PMID: 21769658, 24667779 ), resulting in an unstable mRNA transcript (PMID: 21769658). This variant has been observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 15533909, 20104584, 21769658, 23458327, 24797986, 25452441, 27425403, 30322717) and prostate cancer (PMID: 29368341). This variant has been identified in 1/251154 chromosomes 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. -

Aug 19, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4357+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the BRCA1 gene. This mutation has been reported in multiple individuals with personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Pal T et al. Cancer Epidemiol. Biomarkers Prev. 2004 Nov;13(11 Pt 1):1794-9; Akbari MR et al. Clin. Genet. 2014 Jan;85:64-7; Tihomirova L et al. Adv Med Sci, 2014 Mar;59:114-9; Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11; Alemar B et al. Cancer Genet. 2016 Sep;209:417-422; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). Functional analyses have demonstrated that this alteration leads to a skipping of coding exon 11 (also known as exon 13), causing a frameshift and alternate stop codon (Ambry internal data; Thomassen M et al. Breast Cancer Res. Treat. 2012 Apr;132:1009-23). In addition, this alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). 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. -

Apr 19, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

BRCA1-related cancer predisposition

Pathogenic:1

Aug 29, 2024

All of Us Research Program, National Institutes of Health

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

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.95

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: 1

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