rs757936216

Variant summary

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

The NM_007294.4(BRCA1):​c.927A>T​(p.Lys309Asn) 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. K309E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 missense

Scores

6
9
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.544
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 UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.927A>T p.Lys309Asn missense_variant 10/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.927A>T p.Lys309Asn 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
Uncertain
0.44
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
D;.;.;.;T;T;.;.;T
Eigen
Uncertain
0.26
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Uncertain
0.48
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.58
T
MutationAssessor
Pathogenic
4.0
H;H;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI
Benign
0.36
T
PROVEAN
Pathogenic
-4.6
D;D;D;D;.;D;D;D;D
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
D;D;D;D;.;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;.;D;.;D;D
Polyphen
1.0
D;.;.;D;.;.;.;.;.
Vest4
0.46
MutPred
0.35
Loss of ubiquitination at K309 (P = 0.0087);Loss of ubiquitination at K309 (P = 0.0087);.;Loss of ubiquitination at K309 (P = 0.0087);.;Loss of ubiquitination at K309 (P = 0.0087);.;.;Loss of ubiquitination at K309 (P = 0.0087);
MVP
0.83
MPC
0.49
ClinPred
1.0
D
GERP RS
2.7
Varity_R
0.67
gMVP
0.23

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: chr17-41246621; API