Genetic Variant BRCA1:p.Pro1469Thr (chr17-43079352-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000471181.7(BRCA1):c.4405C>A(p.Pro1469Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. P1469S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BRCA1
ENST00000471181.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.01

Publications

0 publications found

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]

BRCA1 links:

RPL21P4 (HGNC:17959): (ribosomal protein L21 pseudogene 4)

RPL21P4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15677488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.4358-2738C>A		intron_variant	Intron 12 of 22	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.4358-2738C>A		intron_variant	Intron 12 of 22	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.92e-7

AC:

AN:

1444452

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719048

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33410

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5252

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110636

Other (OTH)

AF:

0.00

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.0030

BayesDel_noAF

Benign

-0.24

CADD

Benign

9.8

(source)

DANN

Benign

0.84

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.35

M_CAP

Benign

0.0069

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.61

PhyloP100

4.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.020

REVEL

Benign

0.24

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.043

Vest4

0.39

MutPred

0.16

Gain of phosphorylation at P1469 (P = 0.0213);

MVP

0.72

MPC

0.091

ClinPred

0.37

GERP RS

0.36

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over