chr17-43093738-A-T

Position:

• chr17-43093738-A-T

Variant summary

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

The ENST00000357654.9(BRCA1):​c.1793T>A​(p.Leu598*) 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. L598L) 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:11
• Conservation: PhyloP100: 0.913

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]

BRCA1 (HGNC:):

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 17-43093738-A-T is Pathogenic according to our data. Variant chr17-43093738-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 54351.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093738-A-T is described in Lovd as [Pathogenic]. Variant chr17-43093738-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1793T>A	p.Leu598*	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.1793T>A	p.Leu598*	stop_gained	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 02, 2021	_x000D_ Criteria applied: PVS1, PS4_MOD, PM5, PM2_SUP -
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	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 02, 2022	The p.L598* pathogenic mutation (also known as c.1793T>A) located in coding exon 9 of the BRCA1 gene, results from a T to A substitution at nucleotide position 1793. This changes the amino acid from a leucine to a stop codon within coding exon 9. This mutation has been reported in multiple individuals with histories consistent with hereditary breast/ovarian cancer syndrome (Norquist B et al. J. Clin. Oncol. 2011 Aug; 29(22):3008-15; Ratajska M et al. J. Appl. Genet. 2015 May;56(2):193-8; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238). 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	curation	Sema4, Sema4	Feb 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 12, 2023	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in two individuals affected with ovarian and/or endometrial cancer (PMID: 21709188, 25366421), a suspected hereditary breast and ovarian cancer (PMID: 28324225) and has been identified in 3 families among the CIMBA participants (PMID: 29446198; https://cimba.ccge.medschl.cam.ac.uk/). 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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2024	PM2, PM5_strong, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2024	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 21709188, 25366421, 28324225); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1912T>A; This variant is associated with the following publications: (PMID: 35988656, 31528241, 21205087, 21709188, 25366421, 28324225, 20104584, 29446198, 29254167, 19047089) -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This sequence change creates a premature translational stop signal (p.Leu598*) 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 and/or ovarian cancer (PMID: 25366421, 29254167). ClinVar contains an entry for this variant (Variation ID: 54351). 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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.033
FATHMM_MKL	Benign	0.15	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;N;N;N;N;N;N;N;N
Vest4		0.82
GERP RS		2.8

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: rs80357118; hg19: chr17-41245755;