rs397507243

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_007294.4(BRCA1):​c.5122G>T​(p.Ala1708Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1708E) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 missense

Scores

8
7
4

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 4.86
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 Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 16 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43063903-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 55407.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.5122G>T p.Ala1708Ser missense_variant 17/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.5122G>T p.Ala1708Ser missense_variant 17/231 NM_007294.4 P4P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Other:1
not provided, no classification providedin vitroBrotman Baty Institute, University of Washington-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.33
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
.;T;.;.;T;T;.;.;.;T;.
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.79
D
MutationAssessor
Uncertain
2.8
.;M;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-2.2
N;N;.;N;.;.;N;N;N;N;N
REVEL
Uncertain
0.63
Sift
Uncertain
0.0020
D;D;.;D;.;.;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;.;.;D
Polyphen
0.019, 1.0
.;B;.;.;.;D;.;.;.;D;.
Vest4
0.77
MVP
0.94
MPC
0.39
ClinPred
0.90
D
GERP RS
5.8
Varity_R
0.69
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397507243; hg19: chr17-41215921; API