rs80357511

Positions:

• chr17-43092337-T-TC

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.3193_3194insG​(p.Asp1065GlyfsTer2) 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:11
• Conservation: PhyloP100: -0.591

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 17-43092337-T-TC is Pathogenic according to our data. Variant chr17-43092337-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 54796.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3193_3194insG	p.Asp1065GlyfsTer2	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3193_3194insG	p.Asp1065GlyfsTer2	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 08, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 07, 2022	- -
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)	May 29, 2002	- -
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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2019	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; Observed in individuals with a personal and family history consistent with pathogenic variants in this gene (Werness 2000, Plaskocinska 2016); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.3312dupG; This variant is associated with the following publications: (PMID: 11109172, 17688236, 27208206) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 04, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2022	The c.3193dupG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of G at nucleotide position 3193, causing a translational frameshift with a predicted alternate stop codon (p.D1065Gfs*2). This mutation (designated as 3312insG) was previously identified in a 16-year-old woman with an ovarian dysgerminoma and family history of early onset breast, ovarian, and skin cancer (Werness BA et al. Int. J. Gynecol. Pathol. 2000 Oct; 9:390-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 30, 2020	This variant inserts 1 nucleotide 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 individuals affected with ovarian and breast cancer (PMID: 17688236; Color internal data) and in suspected hereditary breast and ovarian cancer families (PMID: 16267036, 21913181) and is reported to segregate with breast, ovarian and skin cancer in one family (PMID: 11109172). 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: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	Sep 14, 2023	This sequence change creates a premature translational stop signal (p.Asp1065Glyfs*2) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and skin cancer (PMID: 11109172). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3312insG. ClinVar contains an entry for this variant (Variation ID: 54796). For these reasons, this variant has been classified as Pathogenic. -

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: rs80357511; hg19: chr17-41244354;