rs80357303

chr17-43071113-T-Achr17-43071113-T-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):c.4801A>T(p.Lys1601Ter) 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. K1601K) has been classified as Likely benign. 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:10
• Conservation: PhyloP100: 2.60

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 20 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-43071113-T-A is Pathogenic according to our data. Variant chr17-43071113-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 55290.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43071113-T-A is described in Lovd as [Pathogenic]. Variant chr17-43071113-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4801A>T	p.Lys1601Ter	stop_gained	15/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4801A>T	p.Lys1601Ter	stop_gained	15/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 18, 2006	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 23, 2003	- -
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, criteria provided, single submitter	clinical testing	Counsyl	Dec 05, 2016	- -

Breast neoplasm Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3DMed Clinical Laboratory Inc	May 21, 2018	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	Nov 01, 2015	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

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	Invitae	Oct 09, 2018	Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 18006916, 28724667, 27257965, 22776961, 26221963, 25480878, 28294317). Additionally, this variant has been reported in an individual with ovarian cancer who was also affected with thyroid cancer (PMID: 26402875). This variant is also known as A4920T and 4920A>T in the literature (PMID: 18006916, 26402875, 25480878). ClinVar contains an entry for this variant (Variation ID: 55290). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys1601*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2022

The p.K1601* pathogenic mutation (also known as c.4801A>T), located in coding exon 14 of the BRCA1 gene, results from an A to T substitution at nucleotide position 4801. This changes the amino acid from a lysine to a stop codon within coding exon 14. This mutation, also referred to as 4920A>T in the literature, has been seen in multiple patients with a personal and family history of breast and ovarian cancer, including multiple individuals of Asian ancestry (Schrader KA et al. Obstet Gynecol 2012 Aug;120(2 Pt 1):235-40; Ang P et al. Cancer Epidemiol. Biomarkers Prev. 2007 Nov;16(11):2276-84; Choi MC et al. Int. J. Gynecol. Cancer 2015 Oct;25(8):1386-91; Zhang J et al. Breast Cancer Res. Treat. 2016 Aug;158(3):455-62; Kwon BS et al. Cancer Res Treat 2018 Oct; Shi T et al. Int. J. Cancer 2017 05;140:2051-2059; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. 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. -

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	0.99
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.35	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;D;D;D;D
Vest4		0.88
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357303; hg19: chr17-41223130;