17-43074523-T-G

Variant names:

• chr17-43074523-T-G
• rs80358054
• NM_007294.4:c.4485-2A>C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.4485-2A>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. 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: 31)
• Consequence: BRCA1 NM_007294.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.42

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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) 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
• PP5: Variant 17-43074523-T-G is Pathogenic according to our data. Variant chr17-43074523-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 567954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43074523-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4485-2A>C		splice_acceptor_variant, intron_variant	Intron 13 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4485-2A>C		splice_acceptor_variant, intron_variant	Intron 13 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Apr 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 14, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Not found in the total gnomAD dataset, and the data is high quality. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 08, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an A to C nucleotide substitution at the -2 position of intron 13 of the BRCA1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, two different canonical splice site variants at this acceptor site, c.4485-1G>A and c.4485-1G>T, have been shown to cause out-of-frame splicing in RNA analysis of tumor- and carrier-derived RNA (PMID: 26622941, 31843900). This variant has been detected in at least four individuals affected with ovarian or breast cancer (PMID: 30078507, 31825140, 32850417, 34254208). Other canonical splice site variants at this splice acceptor site have been reported as disease-causing in ClinVar (variation ID: 55213, 55214, 246501, 267551, 433715) and detected in individuals affected with breast or ovarian cancer (PMID: 9333265, 11595708, 12181777, 12960223, 24249303, 27553291, 28179634, 29446198, 30287823, 31528241, 33471991; Leiden Open Variation Database DB-ID BRCA1_004959). 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:1

Jun 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 13 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 or undergoing testing for hereditary breast and/or ovarian cancer (PMID: 26622941, 29446198, 30078507). ClinVar contains an entry for this variant (Variation ID: 567954). Studies have shown that disruption of this splice site results in activation of cryptic splice site and introduces a premature termination codon (PMID: 26622941). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	34
DANN	Benign	0.88
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.81	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.59		Position offset: -31
DS_AL_spliceai		0.96		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358054; hg19: chr17-41226540;