GeneBe

NM_007294.4:c.1016delA

Variant names:
GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.
>+14 Pathogenic
-7
-6
-1
0
+5
+6
+9
+10
B
LB
VUS
LP
P
 The variant received 18 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Very_Strong

The NM_007294.4(BRCA1):c.1016delA (p.Lys339ArgfsTer2) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,720 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:15U:1O:1

Conservation

PhyloP100: 0.0760

Publications

3 publications found
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]
BRCA1 Gene-Disease associations (from GenCC):
  • BRCA1-related cancer predisposition
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • breast-ovarian cancer, familial, susceptibility to, 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • Fanconi anemia, complementation group S
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
  • 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

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_007294.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 18 points.

PVS1Null variant in LOF gene
Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 10 of 23) at amino acid 339 of 1863, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~339 amino acids (1524 amino acids lost).
PM2Absent/extremely low in population databases
Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (base 0.0001, raised to 0.000118 by highest known P/LP ClinVar AF 0.000118) — PM2 moderate.
PP5Reputable source reports pathogenic
ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (15/16 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

BRCA1 NM_007294.4
MANE Select
HGVSc / HGVSpc.1016delAp.Lys339ArgfsTer2
Exon rankExon 10 of 23
frameshift
Prot: NP_009225.1UniProt: P38398-1
BRCA1 NM_001407581.1
HGVSc / HGVSpc.1016delAp.Lys339ArgfsTer2
Exon rankExon 10 of 24
frameshift
Prot: NP_001394510.1UniProt: A0A2R8Y7V5
BRCA1 NM_001407582.1
HGVSc / HGVSpc.1016delAp.Lys339ArgfsTer2
Exon rankExon 10 of 24
frameshift
Prot: NP_001394511.1UniProt: A0A2R8Y7V5

Ensembl Transcripts

BRCA1 ENST00000357654.9
TSL:1MANE Select
HGVSc / HGVSpc.1016delAp.Lys339ArgfsTer2
Exon rankExon 10 of 23
frameshift
Prot: ENSP00000350283.3UniProt: P38398-1
BRCA1 ENST00000471181.7
TSL:1
HGVSc / HGVSpc.1016delAp.Lys339ArgfsTer2
Exon rankExon 10 of 24
frameshift
Prot: ENSP00000418960.2UniProt: P38398-7
BRCA1 ENST00000470026.6
TSL:1
HGVSc / HGVSpc.1016delAp.Lys339ArgfsTer2
Exon rankExon 10 of 23
frameshift
Prot: ENSP00000419274.2UniProt: P38398-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)
Rare (AF ≤ 0.0001 / Hom ≤ 1)
Global population databases 3 sources
GnomAD3 genomes
Cov:32
GnomAD4 exome
AF: 6.84e-7
AC:1
Hom:0
AN:1461720
Cov:34
GnomAD4 genome
Cov:32
Showing 3 sources

Case/control cohorts

CohortCasesControls
AFACANAFACAN
SCHEMA
(Schizophrenia)
 0.0000148 167764 0.00 0133118
Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
6
-
-
Breast-ovarian cancer, familial, susceptibility to, 1 (7)
3
-
-
Hereditary breast ovarian cancer syndrome (3)
3
-
-
not provided (3)
2
-
-
Hereditary cancer-predisposing syndrome (2)
1
-
-
Breast and/or ovarian cancer (1)
-
1
-
Malignant tumor of breast (1)

Computational Scores

Mutation Taster
N/A0/200disease causing (ClinVar)
PhyloP100
Benign0.076
Showing 2 of 2 scores

Splicing Scores

SpliceAI score (max)
Benign0.0
Details are displayed if max score is > 0.2
Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

Other links and lift over

dbSNP: rs80357569;
hg19: chr17-41246531;
COSMIC: COSV58791509;
COSMIC: COSV58791509;
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