rs80357305

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000357654.9(BRCA1):​c.4258C>T​(p.Gln1420Ter) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. Q1420Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
ENST00000357654.9 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic reviewed by expert panel P:16

Conservation

PhyloP100: 2.74
Variant links:
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]

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ACMG classification

Classification made for transcript

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 17-43082503-G-A is Pathogenic according to our data. Variant chr17-43082503-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55155.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43082503-G-A is described in Lovd as [Pathogenic]. Variant chr17-43082503-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.4258C>T p.Gln1420Ter stop_gained 12/23 ENST00000357654.9 NP_009225.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.4258C>T p.Gln1420Ter stop_gained 12/231 NM_007294.4 ENSP00000350283 P4P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000202
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8
Pathogenic, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Sep 08, 2016Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Apr 24, 2013- -
Pathogenic, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)Jun 22, 1999- -
Pathogenic, criteria provided, single submitterresearchInstitute of Genomics, University of Tartu-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingConsortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of CambridgeOct 02, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGeneKor MSAJan 01, 2020This variant is a single amino acid change from Glutamine to a Termination codon at amino acid residue 1420 of the BRCA1 gene. It is expected to result in a truncated, non-functional protein. This variant is also known as c.4377C>T in the literature has been reported in patients with breast and/or ovarian cancer (PMID: 18627636, 26306726). The mutation database ClinVar contains entries for this variant (Variation ID: 55155). -
Pathogenic, no assertion criteria providedclinical testingBRCAlab, Lund UniversityAug 26, 2022- -
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 21, 2021The p.Q1420* pathogenic mutation (also known as c.4258C>T), located in coding exon 11 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4258. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation has been previously reported in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Minucci A et al. Expert Rev. Mol. Diagn. 2015 Aug;15:1383-403; Thirthagiri E et al. Breast Cancer Res. 2008 Jul;10:R59; Wen WX et al. J Med Genet, 2018 02;55:97-103; De Talhouet S et al. Sci Rep, 2020 04;10:7073; Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 4377C>T 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 18, 2022This variant changes 1 nucleotide in exon 12 of the BRCA1 gene, creating a 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 reported in individuals affected with breast and ovarian cancer (PMID: 18627636, 26306726; doi:10.1515/tjb.2019.0424). 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. -
Pathogenic, criteria provided, single submittercurationSema4, Sema4Nov 22, 2021- -
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 16, 2023This sequence change creates a premature translational stop signal (p.Gln1420*) 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 (PMID: 18627636, 21120943, 26306726). This variant is also known as c.4377C>T. ClinVar contains an entry for this variant (Variation ID: 55155). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedresearchResearch Molecular Genetics Laboratory, Women's College Hospital, University of TorontoJan 31, 2014- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 04, 2022Nonsense 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 (Thirthagiri 2008, Minucci 2015, Couch 2015); 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 4377C>T; This variant is associated with the following publications: (PMID: 9796975, 25452441, 25525159, 18627636, 26306726, 29446198, 32341426, 28993434, 30702160) -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMay 04, 2021This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals affected with breast or ovarian cancer in the published literature (PMIDs: 18627636 (2008) and 26306726 (2015)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.95
D
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A;A;A;A;D;D;D
Vest4
0.96
GERP RS
4.5

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80357305; hg19: chr17-41234520; API