rs80356866

Variant names:

• chr17-43091690-G-A
• rs80356866
• NM_007294.4:c.3841C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43091690-G-A
• chr17-43091690-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.3841C>T​(p.Gln1281*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 0.247
• Publications: 25 publications found

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

ACMG classification

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 17-43091690-G-A is Pathogenic according to our data. Variant chr17-43091690-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55022.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	c.3841C>T	p.Gln1281*	stop_gained	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.3841C>T	p.Gln1281*	stop_gained	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6

Apr 20, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 30968603 (2019), 30430080 (2018), 22144684 (2012), 15026808 (2004)). Based on the available information, this variant is classified as pathogenic. -

Dec 08, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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 (Claes 1999, Castra 2014, Caputo 2012, Rvillion 2004, can der Hout 2006); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3960C>T; This variant is associated with the following publications: (PMID: 15799620, 9150151, 28724667, 10595255, 24549055, 22144684, 14709649, 16683254, 11506493, 25722380, 25525159, 8807330, 21305653, 21120943, 28541631, 30702160, 29446198, 30968603, 32341426, 31825140) -

Mar 15, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5

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. -

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

- -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 30, 1999

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 23, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Aug 20, 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.Gln1281*) 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 BRCA1-related conditions (PMID: 10923033, 22144684). ClinVar contains an entry for this variant (Variation ID: 55022). For these reasons, this variant has been 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

- -

Mar 27, 2023

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Oct 19, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in families affected with breast and/or ovarian cancer (PMID: 10595255, 15026808). 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. -

Apr 26, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1281* pathogenic mutation (also known as c.3841C>T and 3960C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3841. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been observed in multiple breast and/or ovarian cancer families (Peelen, T et al. Am J Hum Genet. 1997 May;60(5):1041-9; Claes K et al. Dis. Markers 1999 Oct;15(1-3):69-73; Zhao Q et al. J Gynecol Oncol 2017 Jul;28(4):e39; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119), and has been described as a founder mutation from France, Belgium, and/or Holland (Caputo, S et al. Nucleic Acids Res. 2012 Jan;40(Database issue):D992-1002). 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. -

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 BRCA1 p.Gln1281X variant was identified in 31 of 48000 proband chromosomes (frequency: 0.001) from individuals or families with Hereditary breast and ovarian cancers in a French population (Caputo 2012). The variant was also identified in dbSNP (ID: rs80356866) as “With Pathogenic allele”; in the Clinvar and Clinvitae databases as “pathogenic” by Evidence-based Network for the Interpretation of Germline Mutant Alleles, GeneDX, Consortium of Investigators of Modifiers of BRCA1/2 University of Cambridge, Ambry Genetics, Quest Diagnostics Nichols Institute San Juan Capistrano and Breast Cancer Information. The variant is further identified in the GeneInsight-COGR database as pathogenic by Women’s College Hospital, in COSMIC 1X as variant of unknown origin from a bladder carcinoma and in ARUP Laboratories BRCA Mutations Database as definitely pathogenic. The variant was not identified in LOVD-IARC, the BIC database and the Fanconi Anemia Mutation (LOVD), the Exome Aggregation Consortium (August 8, 2016) databases, the 1000 Genomes Project and the NHLBI GO Exome Sequencing Project. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Gln1281X variant leads to a premature stop codon at position 1281, which is predicted to lead to 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.28	N
PhyloP100		0.25
Vest4		0.85
GERP RS		4.3
PromoterAI		-0.0074	Neutral
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80356866; hg19: chr17-41243707; COSMIC: COSV100525178; COSMIC: COSV100525178;