rs80357580

Variant names:

• chr17-43067648-ATTAG-A
• rs80357580
• NM_007294.4:c.5030_5033delCTAA

Your query was ambiguous. Multiple possible variants found:

• chr17-43067648-ATTAG-A
• chr17-43067648-ATTAG-ATTAGTTAG

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.5030_5033delCTAA​(p.Thr1677IlefsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:31
• Conservation: PhyloP100: 1.93

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 17-43067648-ATTAG-A is Pathogenic according to our data. Variant chr17-43067648-ATTAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 37623.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067648-ATTAG-A is described in Lovd as [Pathogenic]. Variant chr17-43067648-ATTAG-A is described in Lovd as [Pathogenic]. Variant chr17-43067648-ATTAG-A is described in Lovd as [Pathogenic]. Variant chr17-43067648-ATTAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5030_5033delCTAA	p.Thr1677IlefsTer2	frameshift_variant	Exon 16 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5030_5033delCTAA	p.Thr1677IlefsTer2	frameshift_variant	Exon 16 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 30

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: 6.84e-7 AC: 1 AN: 1461274 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726986

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74308

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

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31

Revision: reviewed by expert panel

Submissions by phenotype

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

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

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. -

Apr 18, 2016

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2023

Baylor Genetics

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

- -

Aug 26, 2022

BRCAlab, Lund University

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

- -

Jun 27, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2024

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.. 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/or ovarian cancer, and pancreatic cancer (PMID: 9150149, 21989927, 22144684, 22160602). This variant is also known as 5149del4, ter1678 and c.5149delCTAA. ClinVar contains an entry for this variant (Variation ID: 37623). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:7

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM2, PS4_moderate, PVS1 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 10, 2023

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); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Stoppa-Lyonnet et al., 1997; Schneegans et al., 2012; Solano et al., 2012; de Juan Jimenez et al., 2013; Kang et al., 2015; Rweyemamu et al., 2023); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5149_5152delCTAA; This variant is associated with the following publications: (PMID: 28127413, 22160602, 25863477, 30702160, 30287823, 34290354, 34490083, 34413315, 32455662, 32980694, 32772980, 32438681, 30040829, 28888541, 9150149, 22144684, 21989927, 23961350, 23479189, 26183948, 24916970, 15146557, 26843898, 26083025, 27741520, 22798144, 27553291, 27062684, 29020732, 29339979, 29752822, 28831036, 29907814, 28111427, 31372034, 30309222, 30199306, 32072338, 29625052, 26689913, 33726785, 11597388, 32341426, 32719484, 30875412, 30787465, 30613976, 36139606, 34645131, 35264596, 34063308, 34072659, 36230495, 33403015, 32245699, 32380732, 35908255, 35451682, 35893033, 34657357, 35216584, 33649982, 32694901, 34022715, 32862574) -

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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.5030_5033del; p.Thr1677IlefsTer2 variant (rs80357580), also known as 5149del4 or c.5149delCTAA, is reported in the literature in many individuals affected with breast and/or ovarian cancer, and is reported as a founder variant in the French population (selected publications: Caputo 2012, Guindalini 2022, Kechin 2023, Li 2019, Stoppa-Lyonnet 1997). This variant is also reported in ClinVar (Variation ID: 37623), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting four 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: Caputo S et al. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res. 2012 Jan;40(Database issue):D992-1002. PMID: 22144684. Guindalini RSC et al. Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. Sci Rep. 2022 Mar 9;12(1):4190. PMID: 35264596. Kechin A et al. A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia. Breast Cancer Res Treat. 2023 Jan;197(2):387-395. PMID: 36367610. Li JY et al. Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. Int J Cancer. 2019 Jan 15;144(2):281-289. PMID: 29752822. 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. -

Aug 09, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant causes the premature termination of BRCA1 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In addition, it has been reported in affected individuals with breast and/or ovarian cancer and has been reported as a founder variant in French breast cancer populations (PMIDs: 31372034 (2019), 30128899 (2018), 29907814 (2018), 22144684 (2012), and 9150149 (1997)). Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Jan 03, 2025

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.Thr1677Ilefs*2) 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/or ovarian cancer, and pancreatic cancer (PMID: 9150149, 21989927, 22144684, 22160602). This variant is also known as 5149del4, ter1678 and c.5149delCTAA. ClinVar contains an entry for this variant (Variation ID: 37623). For these reasons, this variant has been classified as Pathogenic. -

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Mar 28, 2022

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.5030_5033delCTAA (p.Thr1677IlefsX2) 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 251382 control chromosomes. c.5030_5033delCTAA has been reported in the literature in numerous individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. 13 clinical submitters via ClinVar have classified the variant as pathogenic, including an expert panel. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

May 06, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5030_5033delCTAA pathogenic mutation, located in coding exon 15 of the BRCA1 gene, results from a deletion of 4 nucleotides at positions 5030 to 5033, causing a translational frameshift with a predicted alternate stop codon (p.T1677Ifs*2). This mutation has been reported in numerous HBOC families and patients with triple negative breast cancer throughout the world (Stoppa-Lyonnet D et al. Am. J. Hum. Genet. 1997 May;60(5):1021-30; Caputo S et al. Nucleic Acids Res. 2012 Jan;40(Database issue):D992-1002; Ghiorzo P et al. Fam. Cancer 2012 Mar;11(1):41-7; Schneegans SM et al. Fam. Cancer 2012 Jun;11(2):181-8; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134(3):1315-26; Kang E et al. Breast Cancer Res. Treat. 2015 May;151(1):157-68; Dodova RI et al. BMC Cancer 2015 Jul;15:523; Rashid M et al. BMC Cancer 2016 08;16(1):673; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3; Abdel-Razeq H et al. BMC Cancer 2018 02;18(1):152). Of note, this alteration is also designated as 5149del4 and 5149delCTAA 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. -

Nov 13, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 nucleotides in exon 16 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 11 individuals affected with breast and/or ovarian cancer (PMID: 22160602, 22798144, 23961350, 23479189, 24916970, 25863477, 29339979, 29409476, 29752822, 29907814, 30128899, 33471991). 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. -

Breast and/or ovarian cancer Pathogenic:1

Nov 04, 2013

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast neoplasm Pathogenic:1

Nov 01, 2015

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Nov 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Malignant tumor of breast Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Thr1677IlefsX2 deletion variant was identified in 39 of 56694 proband chromosomes (frequency: 0.001) from individuals with breast or ovarian cancer (Caputo 2011, Ghiorzo 2012, Solano 2012, Stoppa-Lyonnet 1997, van der Hout 2006). This variant was also identified in the following databases: dbSNP (ID: rs80357862) “With pathogenic allele”, LOVD, UMD (59X as a causal variant), and BIC (17X with clinical importance). The p.Thr1677IlefsX2 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1677 and leads to a premature stop codon at position 1678. This alteration is then predicted to result in a truncated or absent protein and loss of function, 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. -

Familial cancer of breast Pathogenic:1

-

Research and Experiment Center, Meizhou People's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs80357580; hg19: chr17-41219665;