rs80357772

chr17-43094548-CAT-C

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.981_982del(p.Cys328Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T327T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 1.13

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 17-43094548-CAT-C is Pathogenic according to our data. Variant chr17-43094548-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 55772.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094548-CAT-C is described in Lovd as [Pathogenic]. Variant chr17-43094548-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.981_982del	p.Cys328Ter	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.981_982del	p.Cys328Ter	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461844 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_007294.4:c.981_982del (chr17:43094548) in BRCA1 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PP5) this variant classifies as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 03, 2013	- -
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	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 30, 2022	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2020	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 (FitzGerald 1996, Thirthagiri 2008, Kwong 2012, Azzollini 2016, Sun 2017, Wu 2017); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database.; Also known as c.1100_1101delAT; This variant is associated with the following publications: (PMID: 22970155, 28724667, 8531968, 23479189, 27257965, 17922413, 24578176, 27062684, 28692638, 26026974, 24961674, 26187060, 18627636, 26848529, 28993434, 29681614, 29086229, 29487695, 30014164, 30078507, 30702160, 30720863, 28176296, 30093976, 30972954, 30309222, 31815095) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2018	Variant summary: BRCA1 c.981_982delAT (p.Cys328X) 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 (e.g. c.1016dupA (p.Val340fsX6), c.1054G>T (p.Glu352X), c.1091_1092delCT (p.Pro364fsX4)). The variant was absent in 277146 control chromosomes. c.981_982delAT has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer (see e.g. Aretini 2003, Wu 2017). These data indicate that the variant is very likely to be associated with disease. A publication also reported experimental evidence that primary (non neoplastic) mammary epithelial cells (obtained from tumour-free women) carrying the variant, were defective in stalled replication fork repair (i.e. suppression of replication stress) that contributes to tumorigenesis in BRCA1-deficient mammary tissue (Pathania 2014). Five 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 30, 2023	This sequence change creates a premature translational stop signal (p.Cys328*) 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 and ovarian cancer and breast cancer and colon cancer (PMID: 8531968, 22970155, 23479189, 24578176, 24961674, 26026974, 26187060, 26848529, 27257965). This variant is also known as 1100delAT and 981delAT. ClinVar contains an entry for this variant (Variation ID: 55772). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Breast neoplasm Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3DMed Clinical Laboratory Inc	May 31, 2017	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	Nov 01, 2015	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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	Aug 24, 2023	The c.981_982delAT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 981 to 982, causing a translational frameshift with a predicted alternate stop codon (p.C328*). This pathogenic mutation has been reported in multiple unrelated individuals with early onset breast and/or ovarian cancer and has been reported as an Asian founder mutation (Kang PC et al. Breast Cancer Res. Treat., 2014 Apr;144:635-42; Angioni S et al. Gynecol Oncol Case Rep, 2014 Aug;9:21-3; Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71; Cruz-Correa M et al. Hered Cancer Clin Pract, 2017 Jan;15:3; Shi T et al. Int. J. Cancer, 2017 05;140:2051-2059; Wu X et al. Int. J. Gynecol. Cancer, 2017 10;27:1650-1657; Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119; Wen WX et al. J. Med. Genet., 2018 02;55:97-103; Liang Y et al. Med. Sci. Monit., 2018 Apr;24:2465-2475; Li A et al. Gynecol. Oncol., 2018 10;151:145-152; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Deng M et al. Int. J. Cancer, 2019 09;145:1517-1528; Deng H et al. Mol Genet Genomic Med, 2019 06;7:e672; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368). This mutation is also referred to as as 1100_1101delAT in the 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

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Computational scores

Source: dbNSFP v4.3

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: rs80357772; hg19: chr17-41246565;