rs80357822

chr17-43092763-ACTGT-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.2764_2767del(p.Thr922LeufsTer77) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 0.557

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 17-43092763-ACTGT-A is Pathogenic according to our data. Variant chr17-43092763-ACTGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 54675.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092763-ACTGT-A is described in Lovd as [Pathogenic]. Variant chr17-43092763-ACTGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2764_2767del	p.Thr922LeufsTer77	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2764_2767del	p.Thr922LeufsTer77	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

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

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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
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	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 18, 2020	This frameshift variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals and families affected with breast or ovarian cancer (PMID: 29021639 (2017), 26425718 (2015), 16683254 (2006)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2018	This deletion of four nucleotides in BRCA1 is denoted c.2764_2767delACAG at the cDNA level and p.Thr922LeufsX77 (T922LfsX77) at the protein level. Using alternate nomenclature, this variant may be defined as 2883_2886delACAG, 2883del4, or 2881delGACA. The normal sequence, with the bases that are deleted in brackets, is ACAG[delACAG]TTAA. The deletion causes a frameshift which changes a Threonine to a Leucine at codon 922, and creates a premature stop codon at position 77 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2764_2767delACAG has been observed in individuals with a personal and family history of breast and/or ovarian cancer (van der Hout 2006, Matsuo 2015, Brice?o-Balc?zar 2017). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 27, 2022	The c.2764_2767delACAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides between nucleotide positions 2764 and 2767, causing a translational frameshift with a predicted alternate stop codon (p.T922Lfs*77). This mutation has been reported in 1 of 4,024 families undergoing BRCA1/2 testing based on a personal or family history of breast and/or ovarian cancer (van der Hout AH et al, Hum. Mutat. 2006 Jul; 27(7):654-66). This mutation has also been reported in a 44-year-old woman with a personal and family history of ovarian cancer (Matsuo K et al, Gynecol Oncol Rep 2015 Aug; 13():36-9). In addition to the clinical data presented in the literature, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 29, 2020	This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in one individual each affected with breast cancer (PMID: 29021639) and ovarian cancer (PMID: 26425718) and in a suspected hereditary breast and ovarian cancer family (PMID: 16683254). 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

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Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 16, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 16683254, 26425718, 29021639). This variant is also known as 2883del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 54675). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Thr922Leufs*77) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80357822; hg19: chr17-41244780;