chr17-43092245-G-A

Position:

• chr17-43092245-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000357654.9(BRCA1):​c.3286C>T​(p.Gln1096Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q1096Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 ENST00000357654.9 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 2.09

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 17-43092245-G-A is Pathogenic according to our data. Variant chr17-43092245-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 54818.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092245-G-A is described in Lovd as [Pathogenic]. Variant chr17-43092245-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3286C>T	p.Gln1096Ter	stop_gained	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.3286C>T	p.Gln1096Ter	stop_gained	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

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:5

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. -
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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	A known pathogenic mutation was detected in the BRCA1 gene (c.3286C>T). This sequence change creates a premature translational stop signal (p.Gln1096*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in gnomAD genomes. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 15617999, 25682074, 27157322). In-silico predictions show pathogenic computational verdict based on 5 pathogenic predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL and MutationTaster vs no benign predictions.This variant is also known as c.3405C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 54818) with 8 submissions all of which describe it as pathogenic, 3 stars, reviewed by expert panel. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 01, 2021	- -

Malignant tumor of urinary bladder Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Urology, Hospital Clinic de Barcelona

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2020

Nonsense 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as BRCA1 c.3405C>T; This variant is associated with the following publications: (PMID: 12181777, 15617999, 26083025, 25682074, 25525159, 25722380, 26187060, 28294317, 29446198, 30702160, 31825140, 32885271) -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

BRCA1, EXON11, c.3286C>T, p.Gln1096X, Heterozygous, PathogenicrnThe BRCA1 p.Gln1096X variant was identified in 3 of 2880 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer and was not identified in 400 control chromosomes from healthy individuals (Liede 2002, Majdak 2005, Wong-Brown 2015). The variant was also identified in the following databases: dbSNP (ID: rs80357485) as "With Pathogenic allele", ClinVar (5x pathogenic), Clinvitae (2x pathogenic), LOVD 3.0 (1x), UMD-LSDB (1x causal), BIC Database (1x pathogenic), and ARUP Laboratories. The variant was not identified in the COGR, Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 1 of 245392 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 1 of 17248 chromosomes (freq: 0.00006), but not in the African, Ashkenazi Jewish, European (Finnish), European (Non-Finnish), Latino, Other, and South Asian populations. The c.3286C>T variant leads to a premature stop codon at position 1096 which is predicted to lead to 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2023

The p.Q1096* pathogenic mutation (also known as c.3286C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3286. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in two individuals with a personal history of epithelial ovarian cancer and triple-negative breast cancer, respectively (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150(1):71-80; Majdak EJ et al. Eur. J. Cancer 2005 Jan;41(1):143-50). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 02, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with breast and ovarian cancer (PMID: 15617999, 25682074, 27157322). ClinVar contains an entry for this variant (Variation ID: 54818). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln1096*) 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.46
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.54	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;D;D;D;D;D;D;D;D
Vest4		0.80
GERP RS		4.2

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: rs80357485; hg19: chr17-41244262;