rs80357724

chr17-43094731-GAA-Gchr17-43094731-GAA-GAchr17-43094731-GAA-GAAA

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.798_799del(p.Ser267LysfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,238 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. VSNL266?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:27
• Conservation: PhyloP100: 0.869

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 17-43094731-GAA-G is Pathogenic according to our data. Variant chr17-43094731-GAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 37698.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094731-GAA-G is described in Lovd as [Pathogenic]. Variant chr17-43094731-GAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.798_799del	p.Ser267LysfsTer19	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.798_799del	p.Ser267LysfsTer19	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459238 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 725554

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 Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 13, 2023	- -
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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 21, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 17, 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, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 16, 2023	The c.798_799del (p.Ser267Lysfs*19) variant of the BRCA1 gene creates an early stop codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast, ovarian and pancreatic cancer, and has been reported to be a founder variant (PMID: 7493024, 17221156, 18159056, 18645608, 20683152, 21324516, 21603858, 22006311, 23233716, 23289006, 24312913, 24606420, 25814778, 26010302, 26864382, 27062684, 29446198, 29506128, 29907814). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in BRCA1 are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, the c.798_799del (p.Ser267Lysfs*19) variant of the BRCA1 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2023	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 individuals with a personal or family history consistent with pathogenic variants in this gene and described as a North African founder variant (Walsh et al., 2011; Uhrhammer et al., 2008; Mahfoudh et al., 2012; Laraqui et al., 2013; De Brakeleer et al., 2015); Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 917_918delTT; This variant is associated with the following publications: (PMID: 22006311, 31921681, 28776284, 33558524, 7493024, 22684231, 25814778, 18645608, 21324516, 15829246, 22425665, 22460208, 26010302, 26864382, 22866093, 27446417, 28212807, 27225819, 26320393, 25780794, 21603858, 23289006, 28478614, 27062684, 29907814, 30606148, 29506128, 31454914, 31447099, 33084842, 32341426, 30787465, 34290354, 32438681, 34646395, 28888541, 33804961) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 14, 2023	The BRCA1 c.798_799del (p.Ser267Lysfs*19) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in multiple individuals and families with breast and/or ovarian cancer and described as a possible North African founder mutation (PMID: 29907814 (2018), 27062684 (2016), 26010302 (2016), 23289006 (2013), 21603858 (2012), 22006311 (2011), 7493024 (1995)). This variant is also reported in an individual with pancreatic cancer (PMID: 29506128 (2018)). 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. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Ser267Lysfs*19) 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 (PMID: 2206311, 7493024, 17221156, 18159056, 18645608, 21324516, 21603858, 23233716, 23289006, 24312913, 25814778, 26010302, 26864382). It is commonly reported in individuals of North Africa including Tunisia, Algeria, and Morocco ancestry (PMID: 2206311, 7493024, 17221156, 18159056, 18645608, 21324516, 21603858, 23233716, 23289006, 24312913, 25814778, 26010302, 26864382). This variant is also known as 917delTT and 916delTT. ClinVar contains an entry for this variant (Variation ID: 37698). 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	Oct 26, 2020	Variant summary: BRCA1 c.798_799delTT (p.Ser267LysfsX19) 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 250012 control chromosomes. c.798_799delTT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven clinical diagnostic laboratories and one expert panel (ENIGMA) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2018	The p.Ser267fs variant in BRCA1 has been reported in over 30 individuals with he reditary breast and/or ovarian cancer (HBOC), segregated with disease in one fam ily, and is reported to be a North African founder variant (Laraqui 2013, Mahfou dh 2012, Cherbal 2010, BIC database: https://research.nhgri.nih.gov/bic/). This variant was absent from large population studies. It is predicted to cause a fra meshift, which alters the protein?s amino acid sequence beginning at position 26 7 and leads to a premature termination codon 19 amino acids downstream. This alt eration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in indiv iduals with HBOC. In addition, this variant has been classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV00028235 0.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon absence from controls, presence in multiple affected individuals, and predicted impact on the protein. ACMG/AMP Criteria applied (Richards 2015): PVS1; PS4; PM2. -

Breast and/or ovarian cancer Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 11, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	May 22, 1997	- -
Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Jun 11, 2019	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 06, 2023	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 been reported in numerous individuals and families affected with hereditary breast and/or ovarian cancer (PMID: 21603858, 23289006, 24312913, 24606420, 25814778, 27062684, 29907814) and is thought to be a founder mutation in the Mediterranean population (PMID: 24312913, 24606420). 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	May 05, 2022	The c.798_799delTT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides between positions 798 and 799, causing a translational frameshift with a predicted alternate stop codon (p.S267Kfs*19). This mutation has previously been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Gayther SA et al. Nat. Genet. 1995 Dec;11(4):428-33; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7; Mahfoudh W et al. Mol. Biol. Rep. 2012 Feb;39(2):1037-46; Laraqui A et al. Int. J. Med. Sci. 2013 Dec;10(1):60-7; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71). It was also seen in a pancreatic cancer cohort (Lowery MA et al. J. Natl. Cancer Inst. 2018 Oct;110(10):1067-1074). Of note, this alteration is also designated as 916delTT 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. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 19, 2016

- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 09, 2021

- -

Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

research

Center of Medical Genetics and Primary Health Care

Apr 08, 2020

ACMG Guidelines 2015 criteria The BRCA1 p.Ser267Lysfs is a known pathogenic frameshift variant in exon 11 in a non-functional domain just before the serine-rich domain (A344-507R aa) and many other downstream domains. This null variant (frame-shift) is predicted to encode a truncated non-functional protein, and heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). It is found in a mutational hotspot of 29 pathogenic variants (PM1 Pathogenic Moderate). The variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV00028235.01) (PP5 Pathogenic Supporting). 1 pathogenic prediction from GERP versus no benign prediction supports its deleterious effect (PP3 Pathogenic Supporting). In this study this variant was found in a 56-year- old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic. -

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: rs80357724; hg19: chr17-41246748;