rs80357296

chr17-43091987-G-Achr17-43091987-G-Cchr17-43091987-G-T

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.3544C>T(p.Gln1182Ter) 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 1.68

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 17-43091987-G-A is Pathogenic according to our data. Variant chr17-43091987-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 54913.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091987-G-A is described in Lovd as [Pathogenic]. Variant chr17-43091987-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3544C>T	p.Gln1182Ter	stop_gained	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3544C>T	p.Gln1182Ter	stop_gained	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 23, 2003	- -
Pathogenic, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	A known pathogenic mutation in the BRCA1 gene was detected in this specimen. This mutation (c.3544C>T) in exon 10 of BRCA1 gene results in a stop codon which causes a truncated non-functional protein. This mutation has 7 entries in ClinVar all of which are listed as pathogenic and not listed in ExAC database. -
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	Sharing Clinical Reports Project (SCRP)	Apr 10, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This sequence change creates a premature translational stop signal (p.Gln1182*) 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 clinical features of hereditary breast and ovarian cancer syndrome (PMID: 29339979, 29446198, 29907814, 30287823). ClinVar contains an entry for this variant (Variation ID: 54913). 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	- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2019

The p.Q1182* pathogenic mutation (also known as c.3544C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3544. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been reported in multiple large studies of BRCA1/2 mutation positive families, including individuals from Norway, Brazil, Japan, Turkey, and Bulgaria (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Palmero EI et al. Sci Rep, 2018 06;8:9188;Momozawa Y et al. Nat Commun, 2018 10;9:4083; Laitman Y et al. Hum. Mutat., 2019 11;40:e1-e23). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	34
Dann	Uncertain	0.98
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.051
FATHMM_MKL	Benign	0.29	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;N;N;N;N;N;N;N;N
Vest4		0.87
GERP RS		4.3

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: rs80357296; hg19: chr17-41244004;