17-43093530-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_007294.4(BRCA1):​c.2001A>T​(p.Gln667His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q667P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 missense

Scores

7
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.148
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.30171692).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.2001A>T p.Gln667His 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.2001A>T p.Gln667His 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
Benign
0.17
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
0.083
DANN
Benign
0.92
DEOGEN2
Uncertain
0.51
D;.;.;.;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.066
N
LIST_S2
Benign
0.77
T;T;T;T;T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.30
T;T;T;T;T
MetaSVM
Benign
-0.30
T
MutationAssessor
Benign
1.9
L;L;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.32
T
PROVEAN
Uncertain
-3.6
D;D;D;D;.
REVEL
Uncertain
0.55
Sift
Benign
0.059
T;T;T;T;.
Sift4G
Uncertain
0.058
T;T;T;T;.
Polyphen
0.61
P;.;.;B;.
Vest4
0.43
MutPred
0.37
Loss of MoRF binding (P = 0.0971);Loss of MoRF binding (P = 0.0971);.;Loss of MoRF binding (P = 0.0971);.;
MVP
0.52
MPC
0.13
ClinPred
0.63
D
GERP RS
-5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.074
gMVP
0.40

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: chr17-41245547; API