17-43092694-ATAC-AG

Position:

• chr17-43092694-ATAC-AG

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.2834_2836delinsC​(p.Ser945ThrfsTer6) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. S945S) has been classified as Likely benign. 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:14
• Conservation: PhyloP100: 0.652

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 17-43092695-TAC-G is Pathogenic according to our data. Variant chr17-43092695-TAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 54694.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.2834_2836delinsC	p.Ser945ThrfsTer6	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2834_2836delinsC	p.Ser945ThrfsTer6	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:14

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)	May 16, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 10, 2016	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 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	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 22, 2020	Variant summary: BRCA1 c.2834_2836delinsC (p.Ser945ThrfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251290 control chromosomes (gnomAD). c.2834_2836delinsC has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Durocher_1996, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submitters including an expert panel (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This sequence change creates a premature translational stop signal (p.Ser945Thrfs*6) 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 present in population databases (rs397509016, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer from the French-Canadian population (PMID: 8933332, 16905680, 21324516, 23621881, 25884701). This variant is also known as 2953del3+C and 2953delGTAinsC. ClinVar contains an entry for this variant (Variation ID: 54694). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2022	This variant replaces 3 nucleotides in exon 10 of the BRCA1 gene with 1 new nucleotide, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with breast and/or ovarian cancer, and is common in the French-Canadian population (PMID: 8933332, 9792861, 10686936, 15382066, 16905680, 21324516, 23621881, 24333842, 25884701). This variant has been identified in 24 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). In a large breast cancer case-control study, this variant has been observed in 0/60466 cases and 1/53460 controls (PMID: 33471991). 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	Jul 22, 2021	The c.2834_2836delGTAinsC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from the deletion of 3 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.S945Tfs*6). This alteration has been recognized as a founder mutation in the French Canadian population, having been identified in multiple individuals and families of French Canadian descent with hereditary breast and/or ovarian cancer (Durocher F et al. J Med Genet 1996 Oct;33(10):814-9; Tonin PN et al. Am J Hum Genet, 1998 Nov;63:1341-51; Oros KK et al. Int. J. Cancer 2004 Nov;112(3):411-9; Ghadirian P et al. Clin Genet 2014 Jan;85(1):31-5; Belanger MH et al. J Ovarian Res 2015;8(1):1). Of note, this alteration is also designated as 2953delGTAinsC in published literature. 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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 28, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 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; Identified in patients with a personal or family history consistent with pathogenic variants in this gene, and is common in the French Canadian population (Durocher 1996, Tonin 1998, Oros 2004, Simard 2007, Ghadirian 2014); 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 2953_2955delGTAinsC; This variant is associated with the following publications: (PMID: 21947752, 8933332, 21324516, 25884701, 15382066, 16905680, 23621881, 9792861, 10422801, 23302520, 24950059, 26941049, 29907814, 30322717, 32300229, 32719484) -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Ser945ThrfsX6 variant was identified in 13 of 3714 proband chromosomes (frequency: 0.004) from individuals of French Canadian families with ovarian and breast cancer (Durocher 1996, Feilotter 2014, Letourneau 2012, Oros 2004, Simard 2007, Zhang 2011), however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified by our laboratory in 8 individuals with ovarian and breast cancer. The variant was also identified in the ClinVar database (classified as a Pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports), the BIC database (9X with clinical importance), and UMD (1X as a causal variant).The p.Ser945ThrfsX6 deletion/insertion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 945 and leads to a premature stop codon 6 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs386134270; hg19: chr17-41244712;