17-43093689-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007294.4(BRCA1):​c.1842G>C​(p.Lys614Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 missense

Scores

5
12
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0200
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.1842G>C p.Lys614Asn missense_variant 10/23 ENST00000357654.9 NP_009225.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.1842G>C p.Lys614Asn missense_variant 10/231 NM_007294.4 ENSP00000350283 P4P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.52
D;.;.;.;T;T;.
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.89
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Uncertain
0.59
D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
3.9
H;H;.;.;.;.;.
MutationTaster
Benign
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Benign
0.38
T
PROVEAN
Pathogenic
-4.5
D;D;D;D;.;D;D
REVEL
Uncertain
0.60
Sift
Uncertain
0.0010
D;D;D;D;.;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;.;D;.
Polyphen
1.0
D;.;.;D;.;.;.
Vest4
0.46
MutPred
0.41
Loss of methylation at K614 (P = 0.0152);Loss of methylation at K614 (P = 0.0152);.;Loss of methylation at K614 (P = 0.0152);.;Loss of methylation at K614 (P = 0.0152);.;
MVP
0.93
MPC
0.49
ClinPred
0.99
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.53
gMVP
0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-41245706; API