rs80358061

chr17-43104967-A-Cchr17-43104967-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):c.213-11T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,606,904 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 2.73

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 12 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-43104967-A-C is Pathogenic according to our data. Variant chr17-43104967-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 37449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43104967-A-C is described in Lovd as [Pathogenic]. Variant chr17-43104967-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.213-11T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.213-11T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250918 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135674

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454670 Hom.: 0 Cov.: 29 AF XY: 0.00000690 AC XY: 5 AN XY: 724192

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: 0.00000723

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

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: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 17, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1994	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 24, 2014	- -
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, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 22, 2023	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change falls in intron 4 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 may result in an absent or disrupted protein product. This variant is present in population databases (rs80358061, gnomAD 0.003%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7894493, 10923033, 18284688, 21993507, 22144684, 25452441). It has also been observed to segregate with disease in related individuals. This variant is also known as c.332-11T>G and IVS5-11T>G. ClinVar contains an entry for this variant (Variation ID: 37449). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 18424508, 23451180; 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	Jul 20, 2017	The c.213-11T>G variant in BRCA1 has been reported in >100 individuals with BRCA 1-associated cancers and has segregated with disease in multiple affected relati ves (Friedman 1994, John 2007, Smith 2012, Wong-Brown 2015, BIC database). This variant has also been reported by multiple clinical laboratories in ClinVar (Var iation ID# 37449). Additionally, this variant has been identified in 3/111540 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org). Sequencing of patient RNA has shown that this variant leads to a retention of 59 base pairs at the 3' end of intron 5, which is predicted to r esult in a premature stop codon (Friedman 1994, Colombo 2013). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individual s with hereditary breast and/or ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the frequency in patients and segregation studies. ACMG/AMP cr iteria applied: PS4, PP1_Strong. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant interpreted as Pathogenic and reported on 11-14-2018 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2016	Variant summary: The BRCA1 c.213-11T>G variant affects a conserved intronic nucleotide. 3/5 splice-site tools predict the variant to create a new cryptic splice site and/or weaken the cononical splice site. This in silico predicted result is proven by multiple functional studies showing that this variant leads to a splicing defect, resulting in an extra 59 base pairs at the end of intron 4 and introducing a premature stop codon. This variant was found in 1/121156 control chromosomes at a frequency of 0.0000083, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). However, the variant has been found in multiple HBOC patients or individuals undergoing BRCA1/2 testing as reported in literature and clinical databases. Additionally, several clinical labs and clinical databases have classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2017	This pathogenic variant is denoted BRCA1 c.213-11T>G or IVS4-11T>G and consists of a T>G nucleotide substitution at the -11 position of intron 4 of the BRCA1 gene. This variant is also known as BRCA1 332-11T>G or BRCA1 IVS5-11T>G using alternate nomenclature. RNA and minigene assays have demonstrated that BRCA1 c.213-11T>G causes aberrant splicing through activation of a cryptic splice acceptor site, introducing a premature stop codon and leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Bonnet 2008, Colombo 2013). This variant has been observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer, and has been shown to segregate with disease (Friedman 1994, Musolino 2005, John 2007, Colombo 2013, Song 2014, Wong-Brown 2015). We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 10, 2019	This variant has been reported in hereditary breast/ovarian cancer families in the published literature (PMIDs: 7894493 (1994), 16457150 (2005), 18159056 (2007), 21170264 (2010), 21993507 (2012), 23451180 (2013), 24728189 (2014), 25682074 (2015), and 27062684 (2016)). RNA splicing studies have shown that this variant interferes with BRCA1 mRNA splicing by activating a cryptic splice-site and causing the inclusion of 59 base pairs of intronic sequence in the BRCA1 mRNA (PMIDs: 18424508 (2008), 22505045 (2012), and 23451180 (2013). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	The BRCA1 c.213-11T>G variant, also known as 332-11T>G or IVS5-11T>G, is reported in the medical literature in multiple individuals and families with breast and/or ovarian cancer (Carter 2018, Friedman 1994, Yost 2019). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37449). This variant is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, in silico analyses and experimental evidence demonstrate this variant causes aberrant intronic splicing (Bonnet 2008, Colombo 2013). Based on available information, this variant is classified as pathogenic. References: Bonnet C et al. Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene. J Med Genet. 2008 Jul;45(7):438-46. PMID: 18424508. Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Colombo M et al. Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. PLoS One. 2013;8(2):e57173. PMID: 23451180. Friedman LS et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet. 1994 Dec;8(4):399-404. PMID: 7894493. Yost S et al. Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers. JNCI Cancer Spectr. 2019 Apr 19;3(2):pkz028. PMID: 31360904. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 05, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 30, 2021	The c.213-11T>G intronic pathogenic mutation results from a T to G substitution eleven nucleotides before coding exon 4 of the BRCA1 gene. In three in vitro studies, this mutation was found to activate a cryptic splice site that leads to the retention of 59 base pairs at the 5' end of coding exon 4, leading to a premature stop codon and a truncated protein product (Colombo M et al. PLoS One. 2013 Mar;8:e57173; Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). In addition, this mutation has been observed in multiple breast and ovarian cancer families to date (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Ellingson MS et al. Breast Cancer Res. Treat. 2015 Sep;153:435-43; Hall MJ et al. Cancer. 2009 May;115:2222-33; John EM et al. JAMA. 2007 Dec;298:2869-76; Musolino A et al. Tumori. 2005 Nov-Dec;91:505-12), including one in which this mutation was reported to segregate with disease through three generations (Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404). Of note, this mutation is also designated as IVS5-11T>G and 75Stop in published literature. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2023	This variant causes a T to G nucleotide substitution at the -11 position of intron 4 of the BRCA1 gene. RNA studies have shown that this variant causes retention of 59 nucleotides at the 3' end of intron 4 (PMID: 18424508, 23451180). This is expected to create a frameshift and premature translation stop signal, resulting in an absent or non-functional protein product. This variant has been reported to segregate with disease in a large family affected with breast and ovarian cancer (PMID: 7894493), and has been observed in several unrelated individuals affected with breast, ovarian and/or endometrial cancer (PMID: 18284688, 21993507, 25452441, 10923033, 22144684, 33484353, 34072659). This variant has also been identified in 3/250918 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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Jan 26, 2007

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 48
DS_AL_spliceai		0.71		Position offset: -11

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358061; hg19: chr17-41256984;