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rs1799950

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_007294.4(BRCA1):c.1067A>T(p.Gln356Leu) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q356R) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 missense

Scores

2
10
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.37
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43094465-G-CCTTATTCCATC is described in ClinVar as [Pathogenic]. Clinvar id is 1781934.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.1067A>T p.Gln356Leu missense_variant 10/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.1067A>T p.Gln356Leu missense_variant 10/231 NM_007294.4 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
0.14
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Uncertain
-0.010
Cadd
Benign
20
Dann
Uncertain
0.98
DEOGEN2
Uncertain
0.52
D;.;.;.;T;T;.;.;T
Eigen
Benign
-0.061
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.82
T;T;T;T;T;T;T;T;T
M_CAP
Uncertain
0.27
D
MetaRNN
Uncertain
0.44
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Uncertain
2.9
M;M;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Pathogenic
-5.6
D;D;D;D;.;D;D;D;D
REVEL
Uncertain
0.41
Sift
Uncertain
0.015
D;D;D;D;.;D;D;D;D
Sift4G
Uncertain
0.025
D;D;D;D;.;D;.;D;D
Polyphen
0.94
P;.;.;D;.;.;.;.;.
Vest4
0.47
MutPred
0.36
Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);.;Gain of helix (P = 0.0078);.;Gain of helix (P = 0.0078);.;.;Gain of helix (P = 0.0078);
MVP
0.84
MPC
0.42
ClinPred
0.88
D
GERP RS
3.7
Varity_R
0.17
gMVP
0.10

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: chr17-41246481; API