chr17-43093496-T-A

Variant names:

• chr17-43093496-T-A
• rs80357082
• NM_007294.4:c.2035A>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.2035A>T​(p.Lys679*) 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:23 O:1
• Conservation: PhyloP100: 0.858
• Publications: 16 publications found

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]

BRCA1 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 54442.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2035A>T	p.Lys679*	stop_gained	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.2035A>T	p.Lys679*	stop_gained	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:9

Jul 02, 2015

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 10, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:4 Other:1

Nov 08, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

not provided Pathogenic:4

Jul 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 the Genome Aggregation Database (v2.1.1), 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. PMID: 24504028. 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. PMID: 11810084. 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. PMID: 9333265. 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. PMID: 22006311. -

Sep 02, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 17, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.2035A>T (p.Lys679*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in multiple individuals and families with breast, ovarian, endometrial and fallopian tube cancers (PMIDs: 36744932 (2023), 29446198 (2018), 26681312 (2015), 24504028 (2014), 21913181 (2012), 22006311 (2011), 21913181 (2011), 21324516 (2011), 20104584 (2010), 11810084 (2002), 9333265 (1997)). In a large scale breast cancer association study, this variant has been observed in one breast cancer case and no reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Breast and/or ovarian cancer Pathogenic:2

Oct 05, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2000

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 01, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 cancer predisposition Pathogenic:1

Apr 25, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

BRCA1-related disorder Pathogenic:1

Jun 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 c.2035A>T variant is predicted to result in premature protein termination (p.Lys679*). This variant (also described as c.2154A>T) has been reported in individuals with hereditary breast and ovarian cancer (Shattuck-Eidens et al. 1997. PubMed ID: 9333265; Walsh et al. 2011. PubMed ID: 22006311; Table S1, Cunningham et al. 2014. PubMed ID: 24504028). This variant has not been reported in the gnomAD database and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/54442/). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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
PhyloP100		0.86
Vest4		0.79
GERP RS		4.2
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80357082; hg19: chr17-41245513;