rs80357347

Positions:

• chr17-43063347-T-A
• chr17-43063347-T-C
• chr17-43063347-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.5179A>T​(p.Lys1727Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,840 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 3.31

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 17-43063347-T-A is Pathogenic according to our data. Variant chr17-43063347-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 37645.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063347-T-A is described in Lovd as [Pathogenic]. Variant chr17-43063347-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.5179A>T	p.Lys1727Ter	stop_gained	18/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5179A>T	p.Lys1727Ter	stop_gained	18/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458840 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
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. -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 03, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 10, 2012	- -
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	All of Us Research Program, National Institutes of Health	Jan 06, 2024	The c.5179A>T (p.Lys1727*) variant of the BRCA1 gene creates an early stop codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast cancer, ovarian cancer and uterine cancer (PMID: 7493024, 10699917, 11802209, 16287141). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in BRCA1 are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, the c.5179A>T (p.Lys1727*) variant of the BRCA1 gene is classified as pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2020	PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 27, 2021	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In the published literature, the variant has been reported in multiple individuals and families with hereditary breast and/or ovarian cancer (PMID: 29446198 (2018), 16287141 (2005), 11802209 (2002), 10699917 (2000), 7493024 (1995)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in association with BRCA1-related cancers (Gayther et al., 1995; Spitzer et al., 2000; Kroiss et al., 2005; Hahnen et al., 2017; Evans et al., 2022); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5298A>T; This variant is associated with the following publications: (PMID: 11802209, 29446198, 27756336, 10699917, 7493024, 16287141, 28715532, 27150160, 30787465, 30209399, 33758026) -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 02, 2019	The p.Lys1727X variant in BRCA1 has been reported in at least 10 individuals with hereditary breast and/or ovarian cancer (HBOC) and segregated with disease in 1 affected relative (Gayther 1995, Kroiss 2005, Rebbeck 2018, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1727, which is predicted to lead to a truncated or absent protein. Loss-of-function of the BRCA1 gene is an established disease mechanism in autosomal dominant HBOC. In vitro functional studies support an impact on protein function (Findlay 2018). In addition, this variant was classified as Pathogenic by the ClinGen-approved ENIGMA expert panel (Variation ID: 37645). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. -
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	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Lys1727*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary breast cancer (PMID: 7493024, 16287141). It has also been observed to segregate with disease in related individuals. This variant is also known as 5298A>T. ClinVar contains an entry for this variant (Variation ID: 37645). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2021	The p.K1727* pathogenic mutation (also known as c.5179A>T), located in coding exon 17 of the BRCA1 gene, results from an A to T substitution at nucleotide position 5179. This changes the amino acid from a lysine to a stop codon within coding exon 17. This pathogenic mutation has been reported in multiple individuals or families with ovarian and/or breast cancer, as well as in one individual diagnosed with uterine cancer (Gayther SA et al. Nat. Genet., 1995 Dec;11:428-33; Spitzer E et al. Int. J. Cancer, 2000 Feb;85:474-81; Meindl A et al. Int J Cancer, 2002 Feb;97:472-80; Kroiss R et al. Hum Mutat, 2005 Dec;26:583-9; Walker LC et al. Eur J Hum Genet, 2017 04;25:432-438; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Yadav S et al. J Clin Oncol, 2020 05;38:1409-1418; Dorling et al. N Engl J Med. 2021 02;384:428-439). One functional study found that this nucleotide substitution is non-functional 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 5298A>T 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jul 08, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A
Vest4		0.85
GERP RS		5.5

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: rs80357347; hg19: chr17-41215364;