rs730882164

Positions:

• chr17-43092020-T-A
• chr17-43092020-T-C

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.3511A>T​(p.Lys1171Ter) 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:6
• Conservation: PhyloP100: 1.34

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 17-43092020-T-A is Pathogenic according to our data. Variant chr17-43092020-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 183177.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092020-T-A is described in Lovd as [Pathogenic]. Variant chr17-43092020-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.3511A>T	p.Lys1171Ter	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.3511A>T	p.Lys1171Ter	stop_gained	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3

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	Institute of Human Genetics, Medical University Innsbruck	Feb 11, 2015	- -
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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2021

The p.K1171* pathogenic mutation (also known as c.3511A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 3511. This changes the amino acid from a lysine to a stop codon within coding exon 9. This alteration was identified in 2/238 unrelated Austrian individuals with suspected hereditary breast and ovarian cancer (Pölsler L et al. Eur. J. Hum. Genet. 2016 Feb;24:258-62). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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. -

BRCA1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2024

The BRCA1 c.3511A>T variant is predicted to result in premature protein termination (p.Lys1171*). This variant was reported in a large cohort of families tested for BRCA1 variants (Rebbeck et al. 2018. PubMed ID: 29446198). This variant has not been reported in a large population database, indicating this variant is rare. It is classified as pathogenic by several labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/183177/). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 29, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant has been observed in individuals affected with breast or ovarian cancer (PMID: 26014432). ClinVar contains an entry for this variant (Variation ID: 183177). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys1171*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	35
DANN	Uncertain	0.97
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.77	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;N;N;N;N;N;N;N;N
Vest4		0.86
GERP RS		1.8

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: rs730882164; hg19: chr17-41244037;