17-43095847-CTT-CTTT

Position:

• chr17-43095847-CTT-CTTT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_007294.4(BRCA1):​c.668dupA​(p.Ala224fs) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 frameshift, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 0.972

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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43095847-C-CT is Pathogenic according to our data. Variant chr17-43095847-C-CT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 125900.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.668dupA	p.Ala224fs	frameshift_variant, splice_region_variant	9/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.668dupA	p.Ala224fs	frameshift_variant, splice_region_variant	9/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Apr 06, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	-	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 11, 2023	This variant changes 1 nucleotides in exon 9 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in the absence of full-length protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncation variants in the vicinity of exons 8 and 9 have been reported in three individuals affected with high-risk breast cancer and/or ovarian cancer (PMID: 12203997, 12815604, 15642173, 33649982) and in a suspected hereditary breast and ovarian cancer family (PMID: 8764110). In one study, an exon 9 frameshift variant (c.594_597del) has been observed in compound heterozygosity with a known pathogenic missense variant, in an individual diagnosed with Fanconi anemia (PMID: 25472942). This truncation variant was inherited from the mother, who was personally affected with ovarian cancer at age 50 with a positive family history of disease. This presentation suggests that the exon 9 variant contributed to the development of disease. However, two splicing variants c.591C>T and c.594-2A>C that have been demonstrated to cause a premature translation stop signal and have been reported in individuals affected with breast and ovarian cancer, as well as in healthy unaffected individuals (PMID: 16211554, 19892845, 25639900, 27008870). The case-control, health history, tumor pathology and segregation data for the c.594-2A>C variant either indicate that this variant is not pathogenic or that pathogenicity is inconclusive (PMID: 25639900, 27008870). In these carriers, there is a relative increase in the skipping of exons 8 and 9 by pre-mRNA splicing that is expected to cause a small in-frame deletion of 41 amino acids from the reference protein (1884 amino acids) (PMID: 19892845, 27008870). An interpretation of these findings is that a BRCA1 mRNA isoform lacking exons 8 and 9 is normally produced and is functional. This alternate mRNA isoform is expected to be refractory to frameshift, nonsense and splicing defective variants found in exons 8 and 9 (PMID: 27008870). RNA studies have confirmed the appearance of the skipping of exons 8 and 9 in the majority of individuals tested, however, the degree of expression also appears to be highly variable in individuals (PMID: 24569164, 27008870, 28905878, 32133419). Taken together, the available evidence suggests that the expected deleterious effects of this c.668dup variant and other truncation variants occurring in exons 8 and 9 could be ameliorated by the expression of the mRNA isoform lacking exons 8 and 9 that retains normal BRCA1 function. Because of the uncertain clinical consequences of this variant, it is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 29, 2020	The c.668dupA variant, located in coding exon 8 of the BRCA1 gene, results from a duplication of A at nucleotide position 668, causing a translational frameshift with a predicted alternate stop codon (p.A224Gfs*4). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, this variant occurs in an exon that is absent in biologically relevant transcripts (Colombo M et al. Hum. Mol. Genet. 2014 Jul;23:3666-80). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 28, 2022

This premature translational stop signal has been observed in individual(s) with high risk of breast and ovarian cancers (PMID: 29446198). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 125900). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala224Glyfs*4) in the BRCA1 gene. Loss-of-function variants in BRCA1 are expected to be pathogenic (PMID: 20104584). However, an in-frame BRCA1 isoform lacking exons 8 and 9 (also known as exons 9 and 10) is highly expressed in blood from unaffected individuals and in normal breast tissue; this isoform may retain protein function and could functionally rescue loss-of-function variants within exons 8-9 (PMID: 24569164). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357537; hg19: chr17-41247864;