17-43093405-A-AT

Position:

• chr17-43093405-A-AT

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.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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: -0.946

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 17-43093405-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/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2125_2126insA	p.Phe709TyrfsTer3	frameshift_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.2125_2126insA	p.Phe709TyrfsTer3	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
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	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -
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, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	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. -
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	Sep 21, 2020	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 03, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2024	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) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 23, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 10, 2019	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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Mar 27, 2012

- -

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: rs80357871; hg19: chr17-41245422;