17-43106480-A-T

Position:

chr17-43106480-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_007294.4(BRCA1):c.188T>A(p.Leu63*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000312 in 1,603,198 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:21O:1

Conservation

PhyloP100: 5.10

Variant links:

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 links:

BRCA1 (HGNC:):

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 17-43106480-A-T is Pathogenic according to our data. Variant chr17-43106480-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 54381.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43106480-A-T is described in Lovd as [Pathogenic]. Variant chr17-43106480-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.188T>A	p.Leu63*	stop_gained	4/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.188T>A	p.Leu63*	stop_gained	4/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1450986

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722344

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:12Other:1

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 07, 2023	This variant changes 1 nucleotide in exon 4 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 is a common cause of breast and/or ovarian cancer in the Japanese population (PMID: 7627958, 24249303, 26187060, 26439132, 29348823). It has also been observed in affected individuals of non-Asian ancestry (PMID: 27741520, 29339979, 29907814). 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, 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	Counsyl	Feb 14, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 14, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	Japanese founder mutation. -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 08, 2018	The c.188T>A (p.Leu63) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with breast or ovarian cancers (PMID 7627958, 11595708, 19016756, 24249303, 24884479, 26187060). This variant has not been reported in gnomAD. Therefore, the c.188T>A (p.Leu63) variant in the BRCA1 gene is classified as pathogenic. -
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	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 12, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Mar 22, 2016	- -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2017	Variant summary: The BRCA1 c.188T>A (p.Leu63X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant is considered a Japanese founder variant and has been reported in several individuals with personal and family history of HBOC, and was also shown to segregate with the disease (Inoue 1995, Nakamura 2013). This variant is absent in 245910 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
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	Labcorp Genetics (formerly Invitae), Labcorp	Mar 16, 2023	This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7627958, 15168169, 19016756, 24249303, 24884479, 25802882, 26187060, 26439132). It is commonly reported in individuals of Japanese ancestry (PMID: 7627958, 15168169, 19016756, 24249303, 24884479, 25802882, 26187060, 26439132). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu63*) 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 also known as a common cause of breast and/or ovarian cancer in the Japanese populations (PMID: 24249303, 26187060). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 54381). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2017	This variant is denoted BRCA1 c.188T>A at the cDNA level and p.Leu63Ter (L63X) at the protein level. The substitution creates a nonsense variant, which changes a Leucine to a premature stop codon (TTA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also reported as 307T>A using alternate nomenclature, has been reported in individuals with breast and/or ovarian cancer and is considered a Japanese pathogenic founder variant (Inoue 1995, Sekine 2001, Sugano 2008, Hirotsu 2015, Nakamura 2015). We consider BRCA1 Leu63Ter to be pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 29, 2020	This variant changes 1 nucleotide in exon 4 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 is a common cause of breast and/or ovarian cancer in the Japanese population (PMID: 7627958, 24249303, 26187060, 26439132, 29348823). It has also been observed in affected individuals of non-Asian ancestry (PMID: 27741520, 29339979, 29907814). 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	Mar 22, 2024	The p.L63* pathogenic mutation (also known as c.188T>A), located in coding exon 3 of the BRCA1 gene, results from a T to A substitution at nucleotide position 188. This changes the amino acid from a leucine to a stop codon within coding exon 3. This mutation has been reported in numerous studies of individuals with personal and/or family history of breast and/or ovarian cancer and is considered a founder mutation in the Japanese population (Inoue R et al. Cancer Res. 1995 Aug; 55(16):3521-4; Sekine M et al. Clin. Cancer Res. 2001 Oct; 7(10):3144-50; Kawahara M et al. J. Hum. Genet., 2004 May;49:391-5; Sugano K et al. Cancer Sci. 2008 Oct;99(10):1967-76; Hirotsu Y et al. Mol Genet Genomic Med, 2015 Mar;3:121-9; Nakamura S et al. Breast Cancer 2015 Sep;22:462-8; Hirasawa A et al. Oncotarget. 2017 Nov 28;8(68):112258-112267; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Further, a functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Of note, this alteration is also designated as 307T>A 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 neoplasm

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

- -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

Vest4

0.90

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.29

Position offset: -24

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over