rs80357943

chr17-43115735-AT-A

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.124del(p.Ile42TyrfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,372 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. I42I) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 2.14

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: 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 17-43115735-AT-A is Pathogenic according to our data. Variant chr17-43115735-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 54173.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115735-AT-A is described in Lovd as [Pathogenic]. Variant chr17-43115735-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.124del	p.Ile42TyrfsTer8	frameshift_variant	3/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.124del	p.Ile42TyrfsTer8	frameshift_variant	3/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461372 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 12, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 24, 2016	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
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 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 10644434, 21735045, 9150149, 21533383, 22362584, 12845657, 10371344, 20625817, 18528753, 30199306) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 28, 2023	This variant deletes 1 nucleotide in exon 3 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 243delA and c.124delA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in several individuals affected with breast cancer (PMID: 10371344, 12845657, 22362584, 26317927, 28145423, 30199306) and in several suspected hereditary breast and ovarian cancer families (PMID: 9150149, 12124814, 12955716, 29446198, 32614418, 32720237). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 15, 2021	The c.124delA pathogenic mutation, located in coding exon 2 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 124, causing a translational frameshift with a predicted alternate stop codon (p.I42Yfs*8). This variant has been detected in several families with early onset breast and/or ovarian cancer (Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9; de Sanjosé S et al. Int J Cancer, 2003 Sep;106:588-93; Stoppa-Lyonnet D et al. Am J Hum Genet, 1997 May;60:1021-30; Díez O et al. Hum Mutat, 2003 Oct;22:301-12). In addition, this mutation is also designated as 243delA in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2021	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant has been observed in several individuals affected with hereditary breast and ovarian cancer (PMID: 9150149, 21735045, 12955716, 12845657, 29446198). This variant has also been reported as 243delA. ClinVar contains an entry for this variant (Variation ID: 54173). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ile42Tyrfs*8) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80357943; hg19: chr17-41267752;