rs80358094

Positions:

• chr17-43063873-C-A
• chr17-43063873-C-G
• chr17-43063873-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5152+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.00000137 in 1,458,892 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:1
• Conservation: PhyloP100: 4.83

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 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.013769671 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• 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 17-43063873-C-A is Pathogenic according to our data. Variant chr17-43063873-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 55423.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063873-C-A is described in Lovd as [Pathogenic]. Variant chr17-43063873-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5152+1G>T		splice_donor_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5152+1G>T		splice_donor_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458892 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726056

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	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 = 1 -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 30, 2018	The c.5152+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 16 of the BRCA1 gene. This intronic mutation, sometimes referred to as IVS18+1G>T and 5271+1G>T in literature, has been reported in a family with multiple members diagnosed with breast cancer before the age of 60 (Gayther SA et al. Nat. Genet. 1995 Dec;11(4):428-33). Additionally, this alteration has been classified as pathogenic by multifactorial analysis, which integrates in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results to determine a likelihood ratio of pathogenicity (Lindor NM et al. Hum. Mutat. 2012 Jan;33(1):8-21). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. As such, this alteration is classified as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 09, 2020	This variant causes a G to T nucleotide substitution at the +1 position of intron 17 of the BRCA1 gene. This variant is also known as IVS18+1G>T in the literature. RNA study on carrier RNA has reported that this variant resulted in the skipping of exon 17 that partially encodes the BRCT domain (PMID: 30101128), and this variant also is reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least nine families at-risk for hereditary breast and ovarian cancer (PMID: 7493024, 29446198) and additional individuals who underwent cancer genetic testing (PMID: 18375895). Multifactorial analyses have found this variant to be deleterious with posterior probability of 1.0, based in part on likelihood ratio (deleterious) of 7562 from tumor histopathology (PMID: 18375895, 21990134). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 04, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (PMID: 30209399). 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: 21990134). ClinVar contains an entry for this variant (Variation ID: 55423). This variant is also known as 5271+1G>T and IVS18+1G>T. Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7493024, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 17 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The c.5152+1G>T variant in BRCA1 has been reported in at least 11 probands hereditary breast and/or ovarian cancer (HBOC; Gayther 1995, Brovkina 2018, BIC database). It was absent from large population studies. 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 dominant HBOC. In vitro functional studies support an impact on protein function (Findlay 2018). This variant was classified as Pathogenic on Oct 18, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 55423). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS3_Moderate, PS4_Moderate. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 2022

Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor et al., 2012); Observed in individuals with personal and/or family history of BRCA1-related cancers (Gayther et al., 1995; Spurdle et al., 2008; Kim et al., 2012; Brovkina et al., 2018; Nones et al., 2019; Frugtniet et al., 2022); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5271+1G>T and IVS18+1G>T; This variant is associated with the following publications: (PMID: 18375895, 8807330, 25525159, 22798144, 7493024, 9699523, 15345110, 30209399, 33087929, 34657373, 21990134, 30333958, 29446198, 31090900) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.90		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358094; hg19: chr17-41215890;