17-43104961-A-T

Position:

• chr17-43104961-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.213-5T>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: 0.9981
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 5.49

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]

BRCA1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43104961-A-T is Pathogenic according to our data. Variant chr17-43104961-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 254639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.213-5T>A		splice_region_variant, intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.213-5T>A		splice_region_variant, intron_variant		1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Medical Genetics, University Hospital of North Norway	May 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.213-5T>A intronic pathogenic variant results from a T to A substitution 5 nucleotides upstream from coding exon 4 in the BRCA1 gene. This variant was identified in 1 individual in a Norwegian HBOC cohort (Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3). In addition, this variant demonstrated an aberrant partial intron retention event that is predicted to lead to premature termination and nonsense mediated decay (Ambry internal data; Jarhelle E et al. Fam. Cancer, 2017 01;16:1-16); This nucleotide substitution was also non-functional in a high throughput, genome-editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant results in partial intron inclusion, which introduces a premature termination codon (PMID: 27495310). The resulting mRNA is expected to undergo nonsense-mediated decay. Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 30209399). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 254639). This variant has been observed in individual(s) with clinical features of hereditary breast and/or ovarian cancer (PMID: 27495310, 29339979). This variant is not present in population databases (ExAC no frequency). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.75		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: rs886038196; hg19: chr17-41256978;