chr17-43093193-G-A

Position:

• chr17-43093193-G-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.2338C>T​(p.Gln780Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000248 in 1,613,642 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:31
• Conservation: PhyloP100: 6.09

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 17-43093193-G-A is Pathogenic according to our data. Variant chr17-43093193-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 54540.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093193-G-A is described in Lovd as [Pathogenic]. Variant chr17-43093193-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2338C>T	p.Gln780Ter	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.2338C>T	p.Gln780Ter	stop_gained	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250740 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135506

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461616 Hom.: 0 Cov.: 41 AF XY: 0.00000275 AC XY: 2 AN XY: 727086

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74254

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:14

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 15, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 17, 2022	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Jul 21, 2022	ACMG criteria used to clasify this variant: PVS1, PM2, PS4 -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 27, 2021	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Jun 11, 2024	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 22, 2021	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has reported in individuals affected with breast and/or ovarian cancer in the published literature (PMIDs: 9667259 (1998), 11802209 (2002), 16683254 (2006), 21324516 (2011), 22752604 (2012), 29470806 (2018), 30322717 (2018)), as well as in an individual affected with fallopian tube carcinoma (PMID: 22006311 (2011)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2022	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 personal and family history of BRCA1-associated cancers (Friedman 1995, Peelen 1997, Frank 1998, Walsh 2011, Weren 2016, Rashid 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 2457C>T; This variant is associated with the following publications: (PMID: 22970155, 9150151, 27767231, 27153395, 22752604, 8533757, 11773283, 9667259, 16615107, 16234499, 11748305, 21324516, 11597388, 25525159, 23199084, 15515971, 16267036, 14574155, 18563556, 25722380, 22006311, 7663517, 29470806, 29446198, 30720243, 30322717, 31528241, 31825140, 32719484, 33726785) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 30, 2021	The BRCA1 c.2338C>T, p.Gln780Ter variant (rs80356945), has been reported in multiple individuals with breast or ovarian cancer (Hogervorst 1995, Walsh 2011). The variant is described as pathogenic by several sources in the ClinVar database (Variation ID: 54540) and is found in 1 out of 250740 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Hogervorst F et al. Rapid detection of BRCA1 mutations by the protein truncation test. Nat Genet. 1995; 10(2):208-12. 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 22, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2016	The p.Gln780X variant in BRCA1 has been reported in >30 individuals with BRCA1-a ssociated cancers (Hogervorst 1995, Frank 1998, Meindl 2002, van der Hout 2006, Walsh 2011, Zhang 2011, Juwle 2012, Breast Cancer Information Core (BIC) databas e). This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 780, which is predicted to l ead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogeni c on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV0002 82277.1). In summary, this variant meets our criteria to be classified as pathog enic for HBOC in an autosomal dominant manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Gln780*) 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 present in population databases (rs80356945, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7663517, 9667259, 16683254, 21324516, 22006311, 22752604). This variant is also known as 2457C>T, Q780X. ClinVar contains an entry for this variant (Variation ID: 54540). For these reasons, this variant has been classified as Pathogenic. -
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	Oct 01, 2021	Variant summary: BRCA1 c.2338C>T (p.Gln780X) 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 allele was found at a frequency of 4e-06 in 250740 control chromosomes. p.Gln780X has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Friedman_1995, Meindl_2002, Judkins_2005, Juwle_2012, Pennington_2014). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 21, 2022	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 individuals affected with ovarian and breast cancer (PMID: 21324516, 22006311, 22752604, 24240112, 29470806, 30322717, 31076742, 33726785, 9667259, Color internal data). In a large breast cancer case-control study conducted by the Breast Cancer Association Consortium, this variant was reported in 4/60466 cases, 0/53461 controls; p-value=0.128; (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001125). This variant has been identified in 1/250740 chromosomes 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	Mar 17, 2022	The p.Q780* pathogenic mutation (also known as c.2338C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2338. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been reported numerous times in breast and ovarian cancer cohorts of varying ethnicities (Janaviius R. EPMA J. 2010 Sep;1:397-412; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Juwle A and Saranath D Med. Oncol. 2012 Dec;29:3272-81; Singh J et al Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). 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	Apr 21, 2021	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 05, 2022

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Gln780X variant was identified in 7 of 3350 proband chromosomes (frequency: 0.002) from individuals or families with breast and ovarian cancers and was not identified in 100 control chromosomes from healthy individuals (Frank 1998, Hogervorst 1995, Juwle 2012, Zhang 2011). A study looking at MYC oncogene activation in BRCA1 germline vs sporadic breast tumours, found MYC was preferentially amplified in BRCA1 promoter methylated tumours and tumours carrying BRCA1 germline mutations, including the Gln780X, supporting MYC activated progression of BRCA1-associated breast cancers (Grushko 2004). In a Dutch study looking at the distribution of (pre)malignant lesions in both breast and adnexal (ovary and Fallopian tube) tissues of hereditary breast/ovarian high risk patients, compared to controls, the Gln780X mutation was associated with lesions in both the ovaries and Fallopian tubes (Hermsen 2006). The variant was also identified in dbSNP (ID: rs80356945) “With pathogenic/uncertain significance allele”, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The p.Gln780X was also identified in HGMD, ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project (SCRP) derived from Myriad reports; classified as pathogenic by BIC; classified as pathogenic by Counsyl; and unclassified by Invitae), the BIC database (36X with pathogenic clinical importance), GeneInsight VariantWire database (classified as benign by a clinical laboratory)and UMD (1X as a 5-Causal variant). The variant was not identified in any cohorts from the general population, including the 1000 Genome Project, HapMap projects, NHLBI Exome Sequencing Project (Exome Variant Server), or the Exome Aggregation Consortium (ExAC) database; COSMIC, LOVD, Breast Cancer IARC or LOVD-IARC. The p.Gln780X variant leads to a premature stop codon at position 780, 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. -

Ovarian neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;D;D;D;D;D;D;D;D
Vest4		0.90
GERP RS		5.4

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: rs80356945; hg19: chr17-41245210;