17-43063869-C-T

Variant names:

• chr17-43063869-C-T
• rs80358165
• NM_007294.4:c.5152+5G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5152+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1 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 14 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 17-43063869-C-T is Pathogenic according to our data. Variant chr17-43063869-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43063869-C-T is described in Lovd as [Pathogenic]. Variant chr17-43063869-C-T is described in Lovd as [Pathogenic]. Variant chr17-43063869-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5152+5G>A		splice_region_variant, intron_variant	Intron 17 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5152+5G>A		splice_region_variant, intron_variant	Intron 17 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2 Uncertain:1 Other:1

-

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 21, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

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

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Sep 01, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Moderate (RNA), PS3, PM2_Supporting BRCA1:c.5152+5G>A is an intronic variant located close to a canonical splice site.An RNA study performed with carrier blood RNA showed skipping of exon 18 (r.5075_5152del)(PMID:13955719), which is predicted to remove 27 aminoacids in a region critical for protein function (PVS1_Moderate). It is not present in the population database gnomAD v2.1.1 (non-cancer, exome only subset) (PM2_Supporting). The SpliceAI algorithm predicts that the variant impairs the splicing donor site (deltascore: 0.89). In addition, in a clinically calibrated saturation genome editing (SGE) assay, resulted as loss of function variant(PMID: 30209399)(PS3). Moreover, the variant cosegregates with the disease (2 meisosis in 2 families from our internal cohort of patients). In addition, the variant has been identified in the ClinVar (7x pathogenic; 2x likely pathogenic; 1 uncertain significance), LOVD (3x pathogenic; 1x likely pathogenic; 1x uncertain significance; 1x NA) and BRCA Exchange (not yet reviewed) databases. A variant within the same donor motif (with stronger predicition of pathogenicity) has been previously classified as pathogenic. Based on currently available information, the variant c.5152+5G>A should be considered a likely pathogenic variant. -

Jan 28, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G>A nucleotide substitution at the +5 position of intron 17 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have reported that this variant causes the skipping of exon 17 (exon 18 in BIC nomenclature) and the in-frame deletion of 26 amino acids in the BRCT domain (PMID: 12955719, 27886673). A different nucleotide substitution at the +5 position was also shown to cause the skipping of exon 17 (PMID: 31642931). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). The skipped exon contains pathogenic missense variants reported in ClinVar that suggests the encoded protein amino acids are important for protein function (ClinVar variation ID: 55396, 55407, 37638, 55418, 55416, 55414, 55413, 55399, 55392). This variant has been reported in multiple families affected with breast and/or ovarian cancer (PMID: 23479189, 12955719, 27886673) and an individual affected with ovarian cancer (PMID: 28176296). 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 Likely Pathogenic. -

Nov 17, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5152+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 16 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. This variant is sometimes referred to as IVS18+5G>A in the literature. This alteration has been observed in breast and ovarian cancer cohorts (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Shi T et al. Int J Cancer, 2017 05;140:2051-2059). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have shown this alteration to cause coding exon 16 (total exon 18) skipping (Ambry internal data; Campos B et al. Hum Mutat, 2003 Oct;22:337; Rodríguez-Balada M et al. Cancer Genet, 2016 Nov;209:487-492). Another alteration impacting the same donor site (c.5152+1G>C) has been shown to have a similar impact on splicing (Ambry internal data; Wappenschmidt B et al. PLoS One 2012 Dec;7(12):e50800.). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay, GM et al. Nature 2018 10;562(7726):217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:2

Jan 27, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant 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 a personal and/or family history of breast and/or ovarian cancer (PMIDs: 35220195 (2022), 30702160 (2019), 29470806 (2018), 28176296 (2017), 23479189 (2013), 22762150 (2012), 12955716 (2003)). Saturation genome editing reports the variant causes loss of BRCA1 function (PMID: 30209399 (2018)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA1 mRNA splicing. The variant's impact on splicing is additionally supported in the published literature (PMIDs: 25525159 (2015), 12955719 (2003)). Based on the available information, this variant is classified as pathogenic. -

Mar 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay et al., 2018); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect; RNA studies suggest that this variant leads to r.5194_5271del and skipping of exon 18 (Campos et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS18+5G>A; 5271+5G>A; This variant is associated with the following publications: (PMID: 30702160, 31589614, 25525159, 11301010, 9974970, 9738006, 10196224, 9811458, 24389207, 10220405, 25348405, 12955719, 30209399, 35220195, 12955716, 23479189, 29470806, 28176296, 33630411, 31825140) -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Mar 26, 2018

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.5152+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site and one predict a significant weaking effect on the 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, with skipping of exon 18 (Campos_2003). The variant was absent in 246244 control chromosomes (gnomAD). c.5152+5G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Jimenez_2013, Diez_2003, Shi_2017, Campos_2003). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 17 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 likely results in a shortened 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: 12955716, 12955719, 23479189, 29470806). ClinVar contains an entry for this variant (Variation ID: 55427). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (PMID: 12955719, 30209399). This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Ser1715Asn) have been determined to be pathogenic (PMID: 10508480, 11157798, 20516115, 22856468, 28781887, 30209399, 30765603). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Ovarian cancer Pathogenic:1

Jul 11, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358165; hg19: chr17-41215886;