rs80358079

chr17-43057147-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):c.5194-12G>A 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 0.00000137 in 1,459,878 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic reviewed by expert panel P:9 U:1 O:1
• Conservation: PhyloP100: 1.48

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.

• PM2: Very rare variant in population databases, with high coverage
• 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 17-43057147-C-T is Pathogenic according to our data. Variant chr17-43057147-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 55451.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43057147-C-T is described in Lovd as [Pathogenic]. Variant chr17-43057147-C-T is described in Lovd as [Pathogenic]. Variant chr17-43057147-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-43057147-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5194-12G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5194-12G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459878 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726396

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.000183 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 11, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, reviewed by expert panel	curation	ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	Apr 23, 2024	The c.5194-12G>A variant is an intronic variant occurring in intron 19 of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and the SpliceAI predictor score is 0.96, predicting an impact on splicing (score threshold >0.20) (PP3 met). This variant was reported to result in aberrant mRNA splicing by partial retention of intron 19 (PMIDs: 21673748, 21394826). Another study reported the same aberration as well as exon 20 skipping, however it also reported a higher proportion of full length transcript (PMID: 31843900) (PVS1 (RNA) not applied due to conflicting evidence). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1126348153 (based on Cosegregation LR=6.5; Pathology LR=12.7; Co-occurrence LR=1.3; Family History LR=10799731), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PP4_Very strong). -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Likely pathogenic and reported on 02-11-2014 by Lab Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2017	Variant summary: The BRCA1 c.5194-12G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. 2/5 splice prediction tools predict that this variant creates a novel 3' splicing acceptor site. This prediction was confirmed by two independent studies by sequencing cDNA from the patients carrying the variant of interest (Whiley_2011, Wong-Brown_2013). The studies showed that the altered splicing led to the inclusion of 10bp intronic sequence generating a downstream frameshift mutation (p.His1732Phefs). This variant has been reported in multiple patients with breast cancer and family history of HBOC. This variant is absent in 121410 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, including an expert panel. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	This sequence change falls in intron 18 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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10923033, 17924331, 23278966, 25682074). ClinVar contains an entry for this variant (Variation ID: 55451). 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 this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21394826, 21673748; Invitae). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 21, 2020	The c.5194-12G>A intronic variant results from a G to A substitution 12 nucleotides upstream from coding exon 18 in the BRCA1 gene. This alteration has been classified as as a pathogenic mutation 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, and functional assay results (Easton DF et al. Am. J. Hum .Genet. 2007 Nov; 81(5):873-83; Whiley PJ et al. Hum. Mutat. 2011 Jun; 32(6):678-87). Multiple, independent RNA based assays indicate that this variant creates a cryptic splice acceptor site that leads to the insertion of 10 nucleotides and, consequently, a predicted protein frameshift (Ambry internal data; Whiley PJ et al. Hum. Mutat. 2011 Jun; 32(6):678-87; Théry JC et al. Eur. J. Hum. Genet. 2011 Oct; 19(10):1052-8; Wong-Brown MW et al. Clin. Genet. 2013 Nov; 84(5):505-6). This nucleotide position is highly conserved in available vertebrate species. Of note, this alteration is also designated as IVS19-12G>A in published literature. 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	Apr 26, 2021	This variant causes a G to A nucleotide substitution at the -12 position of intron 18 of the BRCA1 gene. RNA studies have shown that this variant causes out-of-frame splicing, resulting in expected premature truncation (PMID: 21394826, 21673748, 23278966, 31843900). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in at least 3 individuals affected with breast cancer (PMID: 23278966, 25682074; Color internal data) and also reported to have segregation and family history likelihood ratios for pathogenicity of 532.1 and 363.1, respectively (PMID: 21394826). 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. -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary breast ovarian cancer syndrome;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Pathogenic	29
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: -2
DS_AL_spliceai		0.76		Position offset: -12

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358079; hg19: chr17-41209164;