rs80357971

Positions:

• chr17-43092848-GTT-G
• chr17-43092848-GTT-GT

Variant summary

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

The NM_007294.4(BRCA1):​c.2681_2682del​(p.Lys894ThrfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,724 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. K894K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:25
• Conservation: PhyloP100: 0.447

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 17-43092848-GTT-G is Pathogenic according to our data. Variant chr17-43092848-GTT-G is described in ClinVar as [Pathogenic]. Clinvar id is 17667.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092848-GTT-G is described in Lovd as [Pathogenic]. Variant chr17-43092848-GTT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2681_2682del	p.Lys894ThrfsTer8	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2681_2682del	p.Lys894ThrfsTer8	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152062 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

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461662 Hom.: 0 AF XY: 0.0000151 AC XY: 11 AN XY: 727110

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: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74262

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:12

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	Sharing Clinical Reports Project (SCRP)	Jun 05, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change deletes two bases from exon 10 of the BRCA1 mRNA (c.2681_2682delAA ) causing a frameshift after codon 894 and the creation of a premature translation stop signal 8 amino acid residues later p.(Lys894Thrfs). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic.This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). This mutation has been described in the mutation database ClinVar (Variation ID:17667) . -
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	Division of Medical Genetics, University of Washington	Aug 09, 2019	This variant leads to a translational frameshift and the introduction of a premature termination codon 8 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of BRCA1 is a well-established mechanism of disease for hereditary breast and ovarian cancer. This variant has been reported in multiple individuals and families with breast and/or ovarian cancer, and is considered a European founder variant (Liede 2000, Scottish/Northern Irish BRCAI/BRCA2 Consortium 2003, Hondow 2011, Walsh 2011, Zhang 2011). Thus, this variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Apr 03, 2023	The BRCA1 c.2681_2682del (p.Lys894ThrfsTer8) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant, which is also known as 2800delAA in published literature, has been reported in several individuals with HBOC-related cancers (PMID: 7894493, 27456091, 22006311, 21324516, 33758026, 34657373) and has also been reported as a Scottish founder mutation (PMID: 10682686). This variant is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 21, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jun 26, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 01, 2017	- -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2019	The p.Lys894ThrfsX8 variant in BRCA1 has been reported in >80 individuals with BRCA1-associated cancers (Friedman 1994, Walsh 2011, Wong-Brown 2016, Zhang 2011, Liede 2000, Breast Cancer Information Core (BIC) database), segregated with disease in >10 affected relatives, and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 894 and leads to a premature termination codon 8 amino acids downstream. This alteration 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 individuals with hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282287.1). In summary, the p.Lys894fs variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Strong, PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Lys894Thrfs*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 BRCA1-related conditions (PMID: 7894493, 12698193, 21324516, 22006311, 23199084). It is commonly reported in individuals of European ancestry (PMID: 7894493, 12698193, 21324516, 22006311, 23199084). This variant is also known as 2800delAA. ClinVar contains an entry for this variant (Variation ID: 17667). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2016	Variant summary: The BRCA1 c.2681_2682delAA (p.Lys894Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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.2685_2686delAA, c.2719_2722delGAAG, c.2766delA). One in silico tool predicts a damaging outcome for this variant and the variant is absent in 121670 control chromosomes. The variant has been reported in the literature and databases in numerous affected individuals, and is considered a European founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Aug 06, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 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 personal or family history consistent with pathogenic variants in this gene (Friedman et al., 1994; Liede et al., 2000; Couch et al., 2015; Nguyen-Dumont et al., 2018; Frugtniet et al., 2022); Not observed at significant frequency 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 2800delAA; This variant is associated with the following publications: (PMID: 25452441, 26884819, 26681312, 27376475, 26848151, 27456091, 31970404, 34662886, 28888541, 10682686, 21324516, 7894493, 22006311, 23199084, 12698193, 25072261, 25782689, 17688236, 28918466, 25085752, 29435075, 29422015, 29339979, 26295337, 16644204, 23269703, 21702907, 30678073, 30322717, 31159747, 31263054, 33087929, 34657373, 32719484) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Lys894ThrfsX8 variant was identified in 19 of 6162 proband chromosomes (frequency: 0.03) from individuals or families with breast and epithelial ovarian cancers, and was not identified in 3810 control chromosomes from healthy individuals. The variant has been identified as a Scottish and northern Irish founder mutation (Song_2014, Janavicius_2010, Consortium_2003, Nanda_2005, Peto_1999). The variant was also identified in dbSNP (ID: rs80357971) as “With Pathogenic allele” and in Clinvar and Clinvitae as pathogenic by Evidence-based Network for the interpretation of Germline Mutant Alleles (ENIGMA) Study description; Quest Diagnostics Nichols Institute San Jaun Capistrano; the Consortium of Investigators of Modifiers of BRCA1/2 Univeristy of Cambridge, Ambry Genetics; Invitae; GeneD;, Breast Cancer Informatin Core; OMIM and Sharing Clinical Reports project. The variant has been further identified in ARUP Laboratories BRCA Mutations Database as definitely pathogenic. The variant was not identified in LOVD-IARC, COSMIC, GeneInsight COGR, the BIC, UMD and Fanconi Anemia Mutation (LOVD) and The Exome Aggregation Consortium databases (August 8, 2016) nor was it identified in the 1000 Genomes Project, and the NHLBI GO Exome Sequencing Project. The p.Lys894ThrfsX8 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 894 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 21, 2023	The BRCA1 c.2681_2682del (p.Lys894Thrfs*8) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 30322717 (2018)), 29422015 (2018), 26884819 (2016), 21324516 (2011), 23199084 (2010), 7894493 (1994)). It has been described as a founder mutation in the Scottish/Irish populations (PMIDs: 12698193 (2003) and 23199084 (2010)). The variant has also been reported in prostate cancer (PMID: 27456091 (2016)), peritoneal cancer (PMID: 22006311 (2011)), as well as in colorectal cancer (PMID: 26681312 (2015)). 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. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 19, 2021	The c.2681_2682delAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 2681 to 2682, causing a translational frameshift with a predicted alternate stop codon (p.K894Tfs*8). This mutation has been identified in multiple breast and/or ovarian cancer families and has been described as a Scottish founder mutation (Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404; Janavicius 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. USA. 2011 Nov;108:18032-7; Pruss D et al. Breast Cancer Res. Treat. 2014 Aug;147:119-32; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Wong-Brown M et al. Hered. Cancer Clin. Pract. 2016 Feb;14:6; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan 10;16:3). Of note, this alteration is also designated as 2800delAA 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 14, 2022	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 over ten individuals affected with breast or ovarian cancer (PMID: 7791869, 7894493, 16644204, 21324516, 25452441, 29422015, 33471991; Leiden Open Variation Database DB-ID BRCA1_001657), including observed co-segregation with breast and ovarian cancer in 8 members of one family across multiple generations (PMID: 7894493). This variant also has been reported in one individual each affected with peritoneal and colorectal cancer (PMID: 22006311, 26681312). This variant has been reported as a founder mutation in the individuals with Scottish ancestry (PMID: 10682686, 12698193). 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	curation	Sema4, Sema4	Sep 13, 2021	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Sep 24, 2003

- -

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: rs80357971; hg19: chr17-41244865;