rs80357729

chr17-43091903-C-CT

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.3627_3628insA(p.Glu1210ArgfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,836 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. L1209L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: -0.0350

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 17-43091903-C-CT is Pathogenic according to our data. Variant chr17-43091903-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 37534.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3627_3628insA	p.Glu1210ArgfsTer9	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3627_3628insA	p.Glu1210ArgfsTer9	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251268 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000242 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:9

Pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 16084575, 16949048, 16455195 , 20033483, 22160602, 22762150, 22798144, 23961350, 23633455, 24728189, 24916970, 27167707, 29446198, 29907814, 30257646, 32019277). This variant has been identified in 2/251268 chromosomes 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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
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	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	The c.3627dup (p.Glu1210Argfs*9) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 16949048, 23633455, 22160602]. This 1 bp duplication in exon 10 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant has not been detected in the ExAC database. This variant thus classified as pathogenic. -
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	Human Genetics Bochum, Ruhr University Bochum	Apr 20, 2023	ACMG criteria used to clasify this variant:PVS1, PS4_SUP, PM2_SUP -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 14, 2012	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Glu1210ArgfsX9 variant in BRCA1 has been reported in >10 individuals with breast and/or ovarian cancer (HBOC; Kim 2006, George 2013, Hirasawa 2017, Li 2018, BIC database). It has also been identified in 2/18370 East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1210 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome. Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37534). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_M. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change creates a premature translational stop signal (p.Glu1210Argfs*9) 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 present in population databases (rs80357729, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 16949048, 22160602, 22382806, 22798144, 23633455). This variant is also known as 3627insA and 3746insA. ClinVar contains an entry for this variant (Variation ID: 37534). 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	Sep 03, 2020	Variant summary: BRCA1 c.3627dupA (p.Glu1210ArgfsX9) 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 allele was found at a frequency of 7.9e-06 in 251602 control chromosomes. c.3627dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Kim_2006, Lecarpentier_2012, Solano_2013, Peixoto_2014). These data indicate that the variant is very likely to be associated with disease. Ten 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 laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 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 association with breast and/or ovarian cancer and is a recurrent variant in Korean populations (Kim et al., 2006; Schneegans et al., 2012; Kim et al., 2012; Solano et al., 2012; Hirasawa et al., 2017; Lerner-Ellis et al., 2021); 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 3746dupA; This variant is associated with the following publications: (PMID: 16949048, 24916970, 28012317, 24728189, 22217648, 22382806, 20950396, 22762150, 17100994, 29348823, 25863477, 11802209, 29907814, 30257646, 29922827, 28888541, 23633455, 22160602, 27836010, 28111427, 28205045, 16084575, 16455195, 23961350, 27488874, 22798144, 30720863, 30078507, 30720243, 30350268, 33087929, 30309222, 31825140, 32455662, 31090900, 31447099, 34657373, 30702160, 34645131, 32885271) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	BRCA1: PVS1, PM2, PS4:Moderate, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 28, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2023	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. This variant has been observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 16084575, 16949048, 16455195 , 20033483, 22160602, 22762150, 22798144, 23961350, 23633455, 24728189, 24916970, 27167707, 29446198, 29907814, 30257646, 32019277). This variant has been identified in 2/251268 chromosomes 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	Apr 22, 2022	The c.3627dupA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of A at nucleotide position 3627, causing a translational frameshift with a predicted alternate stop codon (p.E1210Rfs*9). This mutation has been reported in many Korean breast and ovarian cancer families and may be associated with a Korean founder effect (Kim BY et al. Biochem. Biophys. Res. Commun. 2006 Oct;349:604-10; Schneegans SM et al. Fam. Cancer. 2012 Jun;11:181-8; George J et al. Clin. Cancer Res. 2013 Jul;19:3474-84; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Jang JH et al. J. Hum. Genet. 2012 Mar;57:212-5; Son BH et al. Breast Cancer Res. Treat. 2012 Jun;133:1143-52; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Rebbeck TR et al. Breast Cancer Res. 2016 11;18:112; Park JS et al. Cancer Res. Treat. 2017 Oct;49:1012-1021; Han SH et al. Clin. Genet. 2006 Dec;70:496-501; Ahn SH et al. Cancer Lett. 2007 Jan;245:90-5; Seong MW et al. Clin. Genet. 2009 Aug;76:152-60). This mutation was also detected in 1/230 unselected Japanese women with ovarian cancer (Hirasawa A et al. Oncotarget. 2017 Nov;8:112258-112267) and in a cohort of women diagnosed with triple negative breast cancer (Hoyer J et al. BMC Cancer. 2018 Sep;18:926). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration is also designated as 3746insA 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. -

Ovarian serous surface papillary adenocarcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

3DMed Clinical Laboratory Inc

May 21, 2018

- -

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.Glu1210ArgfsX9 variant was identified in 20 of 10984 proband chromosomes (frequency: 0.002) from Korean and American individuals with breast and ovarian cancer and was not identified in 3738 control chromosomes from healthy individuals (Han 2006 17100994, Jang 2012 22217648, Park 2017 28205045 , Song 2014 24728189, Rebbeck 2016 27836010, Kim 2006 16949048, Park 2017 28111427). The variant was identified in 1 breast cancer case with a pathogenic BRCA2 variant, c.6724_6725delGA (Rebbeck 2016 27836010). The variant was also identified in dbSNP (ID: rs80357729) as “With Pathogenic allele”, in ClinVar (classified pathogenic, reviewed by an expert panel in 2016; submitters: ENIGMA, CIMBA, GeneDx, Invitae, Ambry Genetics, Counsyl, Quest Diagnostics Nichols Institute San Juan Capistrano, Color Genomics, Laboratory Corporation of America, SCRP, BIC), Clinvitae (6x), LOVD 3.0, UMD-LSDB (28x as causal), BIC Database (9x as class 5 pathogenic), ARUP Laboratories (as definitely pathogenic), but was not identified in Cosmic, MutDB, Zhejiang University Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3627dupA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1210 and leads to a premature stop codon 9 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. -

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: rs80357729; hg19: chr17-41243920;