rs80357496

Positions:

• chr17-43057120-T-A
• chr17-43057120-T-C
• chr17-43057120-T-G

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.5209A>T​(p.Arg1737Ter) 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: 31)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 1.67

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 17-43057120-T-A is Pathogenic according to our data. Variant chr17-43057120-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 55458.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43057120-T-A is described in Lovd as [Pathogenic]. Variant chr17-43057120-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5209A>T	p.Arg1737Ter	stop_gained	19/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5209A>T	p.Arg1737Ter	stop_gained	19/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Arg1737X variant was not identified in probands in the literature, but was identified in dbSNP (ID: rs80357496) “With Pathogenic allele”, LOVD, the ClinVar database (submitted by BIC and Invitae), and the BIC database (1X with clinical importance; classified as pathogenic). The p.Arg1737X variant leads to a premature stop codon at position 1737, 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 addition, a functional study by Chang (2009) showed that the variant protein exhibited reduced binding to promoters, suggesting that the variant is likely defective in the BRCA1 transcriptional activation function. Furthermore, a study using evolutionary conservation analysis predicted the variant to have a deleterious effect (Pettigrew 2005). In summary, based on the above information, this variant meets our laboratory’s criteria to be 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	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 20, 2002	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;D
Vest4		0.94
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs80357496; hg19: chr17-41209137;