rs80357941

chr17-43094854-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_007294.4(BRCA1):c.676del(p.Cys226ValfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:19
• Conservation: PhyloP100: 1.77

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-43094854-CA-C is Pathogenic according to our data. Variant chr17-43094854-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 37693.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094854-CA-C is described in Lovd as [Pathogenic]. Variant chr17-43094854-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.676del	p.Cys226ValfsTer8	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.676del	p.Cys226ValfsTer8	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 152086 Hom.: 0 Cov.: 32 FAILED QC

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

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1458230 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725242

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8

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	Institute of Human Genetics, Medical University Innsbruck	Feb 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 19, 2013	- -
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	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 14, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jul 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 31, 2021	This variant deletes 1 nucleotide 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least fifteen individuals and additional families affected with breast and/or ovarian cancer (PMID: 9042907, 12491499, 15146557, 19818148, 22366370, 23772696, 24549055, 26745875, 26852130, 33670479), and haplotype analysis suggests that this may be a founder mutation in hereditary breast and ovarian cancer families of Italian ancestry (PMID: 26852130). 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	Oct 05, 2021	The c.676delT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 676, causing a translational frameshift with a predicted alternate stop codon (p.C226Vfs*8). This pathogenic mutation has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Serova OM et al. Am. J. Hum. Genet. 1997 Mar;60:486-95; Adem C et al. Cancer. 2003 Jan;97:1-11; Miolo G et al. BMC Cancer. 2009 Oct;9:360; Maurac I et al. Int. J. Gynecol. Pathol. 2012 May;31:264-71; Azzollini J et al. Eur J Intern Med. 2016 Jul;32:65-71; Cini G et al. BMC Med. Genet. 2016 Feb;17:11; Artioli G et al. Gynecol Oncol, 2021 Jun;161:755-761). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this mutation is also designated as 795delT 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Cys226Valfs*8) 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 cancer and ovarian cancer (PMID: 9042907, 15146557, 16287141, 22366370, 22498944, 24549055, 26745875, 26852130). It is commonly reported in individuals of Northern Italian ancestry (PMID: 26852130). This variant is also known as 795delT or 794delT. ClinVar contains an entry for this variant (Variation ID: 37693). 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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 17, 2022	Variant summary: BRCA1 c.676delT (p.Cys226ValfsX8) 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 242894 control chromosomes. c.676delT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Judkins_2005, Gorski_2004, Serova_1997). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 01, 2019

The BRCA1 c.676delT; p.Cys226fs variant (rs80357941), also known as 795delT or 794delT, is reported in the literature in numerous individuals with a personal or family history of breast and/or ovarian cancer (Azzollini 2016, Cini 2016, Gorski 2004, Kluz 2018, Levanat 2012, Serova 1997, Singer 2014). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37693). Haplotype analysis indicates this variant may be a founder variant in northeastern Italy (Cini 2016). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Azzollini J et al. Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study. Eur J Intern Med. 2016 Jul;32:65-71. Cini G et al. Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy. BMC Med Genet. 2016 Feb 6;17:11. Gorski B et al. A high proportion of founder BRCA1 mutations in Polish breast cancer families. Int J Cancer. 2004 Jul 10;110(5):683-6. Kluz T et al. Frequency of BRCA1 and BRCA2 causative founder variants in ovarian cancer patients in South-East Poland. Hered Cancer Clin Pract. 2018 Feb 27;16:6. Levanat S et al. Three novel BRCA1/BRCA2 mutations in breast/ovarian cancer families in Croatia. Gene. 2012 May 1;498(2):169-76. Serova OM et al. Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes? Am J Hum Genet. 1997 Mar;60(3):486-95. Singer CF et al. Clinical implications of genetic testing for BRCA1 and BRCA2 mutations in Austria. Clin Genet. 2014 Jan;85(1):72-5. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

May 05, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2022

Frameshift 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 multiple Hereditary Breast/Ovarian Cancer families and has been suggested to be a founder variant from North-East Italy (Serova 1997, Gorski 2004, Kroiss 2005, Levanat 2012, Maurac 2012, Cini 2016, Kluz 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 795delT; This variant is associated with the following publications: (PMID: 15146557, 22366370, 22984553, 9042907, 22498944, 26852130, 16287141, 26843898, 26745875, 28715532, 24549055, 12491499, 16528604, 32719484, 30787465, 32132887, 33478551, 31409081, 29492181, 30441849, 27062684) -

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.Cys226ValfsX8 variant was identified in 8 of 1326 proband chromosomes (frequency: 0.006) from individuals or families with breast or ovarian cancer, and was not identified in 242 control chromosomes from healthy individuals (Adem 2003, Maurac 2012, Miolo 2009, Serova 1997, Singer 2014). The variant was also identified in dbSNP (ID: rs80357941) “With Pathogenic allele, ClinVar database (submitted by Sharing Clinical Reports Project; classified as pathogenic (derived from Myriad reports)), the BIC database (16X with clinical importance), and UMD (2X as a causal variant). In a study by Maurac (2012), a patient with the variant showed loss of heterozygosity of the wildtype allele and presence of the mutated allele in tumour tissue. The p.Cys226ValfsX8 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 226 and leads to a premature stop codon 8 codons downstream. This alteration is then predicted to result in 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs80357941; hg19: chr17-41246871;