rs80357770

Positions:

• chr17-43094140-GTTTT-GCTTTC
• chr17-43094140-GTTTT-GNNNNN
• chr17-43094140-GTTTT-GTTT
• chr17-43094140-GTTTT-GTTTTT

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.1387_1390delinsGAAAG​(p.Lys463GlufsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 3.40

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 17-43094141-TTTT-CTTTC is Pathogenic according to our data. Variant chr17-43094141-TTTT-CTTTC is described in ClinVar as [Pathogenic]. Clinvar id is 54234.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1387_1390delinsGAAAG	p.Lys463GlufsTer17	frameshift_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.1387_1390delinsGAAAG	p.Lys463GlufsTer17	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 22, 2019	Variant summary: BRCA1 c.1387_1390delinsGAAAG (p.Lys463GlufsX17) 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 251096 control chromosomes (gnomAD). The variant, c.1387_1390delinsGAAAG, has been reported in the literature in two Native American families, where one of these families had several cases of ovarian- and breast cancer diagnosed below age 50 years (Liede_2002). Though in this family one affected family member did not carry the variant, and one unaffected family member (66 y.o.) carried it, most of the affected family members were not genotyped (Liede_2002). Another study also reported the variant in a male breast cancer patient (Bradley_2011, conference abstract). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories 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 likely pathogenic. -

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

Pathogenic, reviewed by expert panel

curation

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Dec 15, 2017

Variant allele predicted to encode a truncated non-functional protein. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 26, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 02, 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; 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 1506_1509GAAAG and [1506 A>G; 1510insG]; This variant is associated with the following publications: (PMID: 11933205) -

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.Lys463Glufs*17 variant was identified in the literature in two families of aboriginal descent both with breast and ovarian cancer (reported as 1510insG, 1506A>G) (Liede 2002). The variant was also identified in ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx, ENIGMA and COGR). The variant was not identified in dbSNP, LOVD 3.0, or UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1387_1390delinsGAAAG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 463 and leads to a premature stop codon at position 479. 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 BRCA1 associated cancers 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. -

BRCA1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

The BRCA1 c.1387_1390delinsGAAAG variant is predicted to result in a frameshift and premature protein termination (p.Lys463Glufs*17). This variant has been reported to segregate in two extended Native American kindreds with hereditary breast and ovarian cancer (HBOC; Liede et al 2002. PubMed ID: 11933205). This variant was alternatively described as two separate events occurring on the same allele (in cis): c.1506A>G and c.1510insG. This variant has not been reported in a large population database, indicating it is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/54234/). Furthermore, loss of function variants up and downstream of this position have been reported to be causative for HBOC (Human Gene Mutation Database v2020.4). This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2023

The c.1387_1390delAAAAinsGAAAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from the deletion of 4 nucleotides and insertion of 5 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.K463Efs*17). This alteration, designated as 1510insG and 1506A>G, has been reported in two hereditary breast and ovarian cancer families of Aboriginal descent in Canada (Liede A et al. Hum. Mutat. 2002 Apr;19(4):460). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

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: rs80357770; hg19: chr17-41246158;