rs80357067

chr17-43082422-G-Achr17-43082422-G-Cchr17-43082422-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.4339C>T(p.Gln1447Ter) 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: 0.585

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 17-43082422-G-A is Pathogenic according to our data. Variant chr17-43082422-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55173.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43082422-G-A is described in Lovd as [Pathogenic]. Variant chr17-43082422-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4339C>T	p.Gln1447Ter	stop_gained	12/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4339C>T	p.Gln1447Ter	stop_gained	12/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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:6

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
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.4339C>T). This sequence change creates a premature translational stop signal (p.Gln1447*) 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 observed in several individuals with hereditary breast and/or ovarian cancer (PMID: 17319787, 18489799, 21203900, 31409081). ClinVar contains an entry for this variant (Variation ID: 55173) with 7 submissions, all of which classify it as pathegenic, 3 stars and reviewd by an expert panel. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic. -
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)	Jun 25, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 14, 2021	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Feb 06, 2023

This nonsense variant causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in a family with hereditary breast and/or ovarian cancer (HBOC) (PMID: 17319787 (2007), 21203900 (2011)) and individuals and families with a high risk of HBOC (PMID: 29446198 (2018), 31409081 (2019)). Based on the available information, this variant is classified as pathogenic. -

Familial prostate carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 17, 2023

Variant summary: BRCA1 c.4339C>T (p.Gln1447X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251344 control chromosomes. c.4339C>T has been reported in the literature in at-least one individual affected with Cancer (example, Rebbeck_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29446198). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 23, 2022

This variant changes 1 nucleotide in exon 12 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hereditary breast and/or ovarian cancer (PMID: 17319787, 21203900, 31409081). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55173). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 17319787, 18489799). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1447*) 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	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	34
Dann	Uncertain	0.98
Eigen	Benign	0.11
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.12	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;N;N;N
Vest4		0.90
GERP RS		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80357067; hg19: chr17-41234439;