rs80357082

chr17-43093496-T-A

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.2035A>T(p.Lys679Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,786 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. K679K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:22 O:1
• Conservation: PhyloP100: 0.858

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 17-43093496-T-A is Pathogenic according to our data. Variant chr17-43093496-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 54442.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093496-T-A is described in Lovd as [Pathogenic]. Variant chr17-43093496-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2035A>T	p.Lys679Ter	stop_gained	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2035A>T	p.Lys679Ter	stop_gained	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461786 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727186

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 10, 2017	The c.2035A>T (p.Lys679*) variant in the BRCA1 gene has been reported in multiple patients with breast and/or ovarian cancer [PMID 9333265, 24504028, 11810084, 22006311]. This change was also reported in 34 patients in the Breast Cancer Information Core database. This c.2035A>T (p.Lys679*) variant creates a premature stop codon at amino acid position 679 of the BRCA1 protein and is thus predicted to result in a loss of function of the protein. The c.2035A>T (p.Lys679*) variant has not been reported in the ExAC database. This variant is thus classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
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)	Mar 18, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals and families affected with breast, ovarian and fallopian tube cancer (PMID: 9333265, 11810084, 20104584, 21324516, 22006311, 22010008, 24504028, 26681312, 33471991; Leiden Open Variation Database DB-ID BRCA1_002609). 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. -
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)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Lys679X variant was identified in 2 of 1596 proband chromosomes (frequency: 0.001) from individuals or families with hereditary Breast and Ovarian Cancer (Shattuck-Eidens 1997). The variant was also identified in dbSNP (ID: rs80357082) “With pathogenic allele”, HGMD, the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports, as pathogenic by GeneDX, as pathogenic by BIC and as pathogenic by Ambry Genetics), GeneInsight-VariantWire (1X, classified as pathogenic by a clinical laboratory), the BIC database (34X with clinical importance), and UMD (2X as a pathogenic variant). In addition, the variant was also described in a woman with a primary fallopian tube cancer from a family with a history of hereditary breast and ovarian cancer (Hébert--Blouin 2002). The p.Lys679X variant leads to a premature stop codon at position 679, 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 summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Lys679*) 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 breast and/or ovarian cancer and fallopian tube cancer (PMID: 9333265, 11810084, 21913181, 22006311, 24504028, 26681312). This variant is also known as 2154A>T. ClinVar contains an entry for this variant (Variation ID: 54442). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 08-17-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
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	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 08, 2021	Variant summary: BRCA1 c.2035A>T (p.Lys679X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 254368 control chromosomes (gnomAD). c.2035A>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Borg_2010, Lee 2011, Litton_2011, Walsh_2011, Song 2014, Sand usswein_2015). These data indicate that the variant is associated with disease. Twelve clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Shattuck-Eidens 1997, Hbert-Blouin 2002, Pal 2005, Walsh 2011, Cunningham 2014); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Also known as 2154A>T; This variant is associated with the following publications: (PMID: 22006311, 21993507, 23583677, 20104584, 26681312, 33227068, 9333265, 16284991, 24504028, 25525159, 24728189, 11810084, 21324516, 22010008, 29446198, 31447099, 32885271) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 15, 2019	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in multiple individuals and families with breast, ovarian, and fallopian tube cancers in the published literature (PMID: 29446198 (2018), PMID: 26681312 (2015), PMID: 24504028 (2014), PMID: 21913181 (2012), PMID: 22006311 (2011), PMID: 21913181 (2011), PMID: 21324516 (2011), PMID: 20104584 (2010), PMID: 11810084 (2002), and PMID: 9333265 (1997)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 26, 2021	The BRCA1 c.2035A>T; p.Lys679Ter variant (rs80357082) has been reported in multiple individuals with breast or ovarian cancer (Cunningham 2014, Hebert-Blouin 2002, Shattuck-Eidens 1997, Walsh 2011). This variant is reported as pathogenic by multiple sources in ClinVar (Variation ID: 54442), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Lys679Ter variant is classified as pathogenic. References: Cunningham JM et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014 Feb 7;4:4026. Hebert-Blouin MN et al. Fallopian tube cancer in a BRCA1 mutation carrier: rapid development and failure of screening. Am J Obstet Gynecol. 2002 Jan;186(1):53-4. Shattuck-Eidens D et al. BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA. 1997; 278(15):1242-50. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011; 108(44):18032-7. -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jun 30, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 05, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 14, 2023	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals and families affected with breast, ovarian and fallopian tube cancer (PMID: 9333265, 11810084, 20104584, 21324516, 22006311, 22010008, 24504028, 26681312, 33471991; Leiden Open Variation Database DB-ID BRCA1_002609). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 02, 2021	The p.K679* pathogenic mutation (also known as c.2035A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 2035. This changes the amino acid from a lysine to a stop codon within coding exon 9. This mutation has been reported in multiple familial breast and ovarian cancer kindreds to date (Shattuck-Eidens D et al. JAMA. 1997 Oct;278:1242-50; Hébert-Blouin MN et al. Am. J. Obstet. Gynecol. 2002 Jan;186:53-4; Kauff ND et al. J. Clin. Oncol. 2008 Mar;26:1331-7; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Lee E et al. J. Clin. Oncol. 2011 Nov;29:4373-80; Cunningham J et al. Sci Rep. 2014 Feb;4:4026; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9). Of note, this alteration is also designated as 2154A>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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.065
FATHMM_MKL	Benign	0.20	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;N;N;N;N;N;N;N;N
Vest4		0.79
GERP RS		4.2

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: rs80357082; hg19: chr17-41245513;