rs80358053

chr17-43067607-C-Achr17-43067607-C-Gchr17-43067607-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):c.5074+1G>T variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. 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: 30)
• Consequence: BRCA1 NM_007294.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:10 O:1
• Conservation: PhyloP100: 4.72

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 22 ACMG points.

• PVS1: Splicing 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
• 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 17-43067607-C-A is Pathogenic according to our data. Variant chr17-43067607-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 37630.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067607-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5074+1G>T		splice_donor_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5074+1G>T		splice_donor_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	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 = 0.998992 -
Likely pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 20, 2007	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Apr 12, 1999	- -
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	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 20, 2021	Variant summary: BRCA1 c.5074+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. Three predict the variant abolishes a 3' acceptor site. In a functional study, this variant was reported to lead to inclusion of intronic sequence resulting in early termination of the BRCA1 protein (Brose_2004). The variant was absent in 251352 control chromosomes. c.5074+1G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Juwle_2012, Li_2018, Ryu_2019, Cecener_2020, etc). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 28, 2023	This sequence change affects a donor splice site in intron 16 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15117986, 22752604, 29446198, 30078507, 30350268). This variant is also known as IVS17+1G>T. ClinVar contains an entry for this variant (Variation ID: 37630). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 15345110, 24667779; Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 29, 2020	The c.5074+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 15 of the BRCA1 gene. 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). This alteration was identified in multiple studies of BRCA1/2 mutation positive families (Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Nones K et al. Ann. Oncol., 2019 07;30:1071-1079; Laitman Y et al. Hum. Mutat., 2019 11;40:e1-e23; Kim HN et al. Chonnam Med J, 2019 May;55:99-103; Li A et al. Gynecol. Oncol., 2018 10;151:145-152; Darooei M et al. Tumour Biol., 2017 Feb;39:1010428317694303; Juwle A et al. Med. Oncol., 2012 Dec;29:3272-81; Choi DH et al. J. Clin. Oncol., 2004 May;22:1638-45). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 04, 2022	This variant causes a G to T nucleotide substitution at the +1 position of intron 16 of the BRCA1 gene. This variant is also known as 5193+1G>T and IVS17+1G>T based on Breast Cancer Information Core (BIC) nomenclature. Functional RNA studies have shown that this variant leads to the activation of a cryptic splice site and results in the premature truncation of the BRCA1 protein (PMID: 15345110, 24667779). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals affected with early onset breast cancer and ovarian cancer (PMID: 15117986, 22711857, 22752604, 30078507, 34657357), and has been identified in six families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 02, 2016

This variant is denoted BRCA1 c.5074+1G>T or IVS16+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 16 of the BRCA1 gene. Using alternate nomenclature, this variant has previously been published as BRCA1 5193+1G>T and IVS17+1G>T. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in multiple individuals with a personal and/or family history consistent with Hereditary Breast and Ovarian Cancer (Choi 2004, Kang 2015, Gonzalez-Rivera 2016, Seifert 2016). Brose et al. (2004) performed RT-PCR studies that revealed that this variant produces a truncated protein product. In addition, Steffensen et. al. (2014) used a mingene assay to further evaluate the splicing defect caused by this variant and two aberrant transcripts were observed, both of which are expected to result in a truncated protein product. Based on the current evidence, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	30
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		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: rs80358053; hg19: chr17-41219624; COSMIC: COSV104398475;