rs387906563

chr17-43094706-G-GCCACATGGCT

Variant summary

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

The NM_007294.4(BRCA1):c.824_825insAGCCATGTGG(p.Thr276AlafsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,180 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. G275G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:24 O:1
• Conservation: PhyloP100: 1.57

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 17-43094706-G-GCCACATGGCT is Pathogenic according to our data. Variant chr17-43094706-G-GCCACATGGCT is described in ClinVar as [Pathogenic]. Clinvar id is 55723.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.824_825insAGCCATGTGG	p.Thr276AlafsTer14	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.824_825insAGCCATGTGG	p.Thr276AlafsTer14	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151940 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250772 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 1460240 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726154

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000673

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151940 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74186

Gnomad4 AFR AF: 0.0000967

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 18, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 04, 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, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Oct 18, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	research	Centro de Genética y Biología Molecular, Universidad de San Martín de Porres	Mar 09, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 06, 2021	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 21, 2017	The c.815_824 frameshift change in BRCA1 has been reported in multiple unrelated patients with breast, ovarian or prostate cancer [PMID 9150149, 10417303, 22006311, 15533909]. This variant is classified as pathogenic. It is recommended that the zygosity (heterozygous vs. mosaic) of this change be confirmed by Sanger sequencing as NGS variant calling may lead to skewed allele fractions for an indel of this size. -
Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 05, 2022	PP5, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 01, 2023	This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.0000071 (2/282168 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33646313 (2021), 32341426 (2020), 31331294 (2019), 30262796 (2018)) and ovarian cancer (PMID: 30322717 (2018)). In addition, this variant has been reported as a founder mutation of African origin (PMID: 10417303 (1999), 21120943 (2011), 22762150 (2012)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	BRCA1: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2019	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 has been described as a pathogenic founder variant of African origin (Mefford 1999, Pal 2004, Stoppa-Lyonnet 1997, Walsh 2011, Villarreal-Garza 2015, Rummel 2017); Not observed at a 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 926ins10, 934_943dup10, or 943ins10; This variant is associated with the following publications: (PMID: 26071757, 32025337, 27742776, 22006311, 9150149, 15533909, 10417303, 25920394, 26681312, 25256238, 22739995, 28944232, 28503720, 30262796, 30720243, 30322717, 31331294, 25716084, 31447099, 32832836, 32341426, 33646313) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 13, 2022	The BRCA1 c.815_824dup; p.Thr276AlafsTer14 variant (rs387906563) is reported in multiple individuals affected with breast and ovarian cancer (Mefford 1999, Stoppa-Lyonnet 1997, Walsh 2011, Zayas-Villanueva 2019). This variant is also reported in ClinVar (Variation ID: 55723), and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting 10 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Mefford HC et al. Evidence for a BRCA1 founder mutation in families of West African ancestry. Am J Hum Genet. 1999 Aug;65(2):575-8. PMID: 10417303. Stoppa-Lyonnet D et al. BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Institut Curie Breast Cancer Group. Am J Hum Genet. 1997 May;60(5):1021-30. PMID: 9150149. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. PMID: 22006311. Zayas-Villanueva OA et al. Analysis of the pathogenic variants of BRCA1 and BRCA2 using next-generation sequencing in women with familial breast cancer: a case-control study. BMC Cancer. 2019 Jul 22;19(1):722. PMID: 31331294. -

Hereditary breast ovarian cancer syndrome Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Thr276Alafs*14) 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 (rs387906563, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 9150149, 10417303, 26681312, 28503720). This variant is also known as 926ins10, ter289, and 943ins10. ClinVar contains an entry for this variant (Variation ID: 55723). 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	Jan 30, 2017	Variant summary: The BRCA1 c.815_824dupAGCCATGTGG (p.Thr276Alafs) 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.843_846delCTCA/p.Ser282fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121190 control chromosomes. It has been reported in multiple affected individuals and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	Founder variant in those of West African ancestry -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 13, 2023	The p.Thr276AlafsX14 variant in BRCA1 has been reported in multiple individuals with BRCA1-associated cancers bnand is believed to be a founder variant of African origin (Stoppa-Lyonnet 1997 PMID: 9150149, Mefford 1999 PMID: 10417303, Walsh 2011 PMID: 22006311, Buleje 2017 PMID: 28944232). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 55723) and has been identified in 0.01% (4/41360) of African or African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 276 and leads to a premature termination codon 14 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 autosomal dominant HBOC. In the compound heterozygous or homozygous state, these variants are associated with autosomal recessive Fanconi anemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 01, 2023	This variant inserts 10 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 at least fifteen individuals and over two dozen families affected with breast and ovarian cancer (PMID: 9150149, 10417303, 15533909, 19241424, 20838878, 21120943, 22006311, 21913181, 22739995, 26681312, 28503720, 28944232, 30322717, 32025337, 32341426, 33646313, 34413315) and prostate cancer (PMID: 32832836). Haplotype analysis suggests that this variant may be founder mutation originating from West African (PMID: 10417303, 32025337). This variant has been identified in 2/282168 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	Oct 29, 2018	The c.815_824dup10 pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of AGCCATGTGG at nucleotide position 815, causing a translational frameshift with a predicted alternate stop codon (p.T276Afs*14). This pathogenic mutation has been reported in numerous hereditary breast and ovarian cancer (HBOC) syndrome families, and it has been established as a founder mutation of African origin (Stoppa-Lyonnet D et al. Am. J. Hum. Genet. 1997 May;60:1021-30; Mefford HC et al. Am. J. Hum. Genet. 1999 Aug;65:575-8; Panguluri RC et al. Hum. Genet. 1999 Jul-Aug;105:28-31; Pal T et al. Cancer Epidemiol. Biomarkers Prev. 2004 Nov;13:1794-9; Ferla R et al. Ann. Oncol. 2007 Jun;18 Suppl 6:vi93-8; Zhang J et al. Breast Cancer Res. Treat. 2012 Jul;134:889-94; Jara L et al. Biol. Res. 2017 Oct;50:35). Of note, this alteration is also designated as 943ins10 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

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Dec 18, 2014

- -

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

Dec 01, 2021

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906563; hg19: chr17-41246723;