17-43093405-A-AT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_007294.4(BRCA1):c.2125_2126insA(p.Phe709TyrfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. F709F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:17

Conservation

PhyloP100: -0.946

Publications

13 publications found

Variant links:

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]

BRCA1 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia, complementation group S
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 4
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 17-43093405-A-AT is Pathogenic according to our data. Variant chr17-43093405-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 54469.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.2125_2126insA	p.Phe709TyrfsTer3	frameshift_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.2125_2126insA	p.Phe709TyrfsTer3	frameshift_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:8

May 05, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

A known pathogenic mutation was detected in the BRCA1 gene (c.2125_2126insA). This sequence change creates a premature translational stop signal (p.Phe709Tyrfs*3) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases ( gnomAD). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 10200350, 16905680, 24549055, 25884701, 27083178). This variant is also known as 2244insA in the literature. ClinVar contains an entry for this variant (Variation ID: 54469). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic. This variant was confirmed by Sanger Sequencing . Pathogenic mutations in the BRCA1 gene cause Hereditary Breast/Ovarian Cancer syndrome (HBOC). Carriers of a deleterious BRCA1 gene mutation are at: 50%-80% risk of developing breast cancer [general population at 12%]. 21.1% within 10 yrs and 83% by age 70 risk of developing second primary breast [general population at 2% within 5 years]. 24-%-40% risk of developing ovarian cancer [general population at 1-2%]. 1%-2% risk of developing male breast cancer [general population at 0.1%]. Up to 30% risk developing prostate cancer [general population at 15-18%]. 1%-3% risk developing pancreatic cancer [general population at 0.5%]. The Breast Cancer Linkage Consortium reported statistically significantly increased relative risks for cancers of the uterine body and cervix (only in heterozygous women age <65 years), with relative risks of 2.6, and 3.7 respectively [Thompson & Easton 2002]. Germline pathogenic variants in BRCA1 are inherited in an autosomal dominant manner. The majority of individuals with a BRCA1 pathogenic variant have inherited it from a parent. However, because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from prophylactic surgery, or early death, not all individuals with a BRCA1 pathogenic variant have a parent affected with cancer. -

Nov 25, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

Variant allele predicted to encode a truncated non-functional protein. -

University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Sep 21, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA1 c.2125_2126insA (p.Phe709TyrfsX3) 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 251170 control chromosomes. c.2125_2126insA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Laplcae-Marieze_1999, Simard_2007, 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. Seven 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. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Oct 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Phe709Tyrfs*3) 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 ovarian cancer (PMID: 10200350, 16905680, 24549055, 25884701, 27083178). This variant is also known as 2244insA. ClinVar contains an entry for this variant (Variation ID: 54469). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

May 29, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; 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 2244_2245insA and 2244insA; This variant is associated with the following publications: (PMID: 30145549, 16905680, 25884701, 10200350, 20694749, 24549055, 27446417, 28478614, 32894085, 32300229, 35578052, 27083178, 29446198, 22762150) -

Apr 03, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Sep 10, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant inserts 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. Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has been reported with individuals affected with breast and/or ovarian cancer (PMID: 16905680, 24549055, 25884701, 27083178, 20694749, 28478614). 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. Based on the available evidence, this variant is classified as Pathogenic. -

Jun 23, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2125_2126insA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from an insertion of one nucleotide at position 2125, causing a translational frameshift with a predicted alternate stop codon (p.F709Yfs*3). This alteration has been reported in numerous individuals with personal and/or family history consistent with hereditary breast and ovarian cancer syndrome (Laplace-Marieze V et al. Int. J. Oncol., 1999 May;14:971-7; Simard J et al. J. Med. Genet., 2007 Feb;44:107-21; Lecarpentier J et al. Breast Cancer Res., 2012 Jul;14:R99; Castéra L et al. Eur. J. Hum. Genet., 2014 Nov;22:1305-13; Belanger MH et al. J Ovarian Res, 2015 Mar;8:1; González-Rivera M et al. Breast Cancer Res. Treat., 2016 04;156:507-515; Jouali F et al. Oncol Lett, 2016 Aug;12:1192-1196; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Of note, this alteration is also designated as 2244insA, c.2126insA, and c.2126_2127insA 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. -

Breast and/or ovarian cancer

Pathogenic:1

Mar 27, 2012

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome;C2931038:Familial pancreatic carcinoma

Pathogenic:1

Sep 19, 2014

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.95

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over