17-43094776-C-A

Variant names:

• chr17-43094776-C-A
• ENST00000497488.2:c.-134G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001407966.1(BRCA1):​c.-134G>T variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_001407966.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.881

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17329252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.755G>T	p.Arg252Leu	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.755G>T	p.Arg252Leu	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1

Apr 27, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T;.;.;.;.;.;T;.;T;.;T;T;.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;N;.;N;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.83	N;N;N;N;N;N;N;N;D;N;.;N;N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D;D;T;D;T;D;D;D;D;D;.;D;D;D
Sift4G	Benign	0.21	T;T;T;T;T;.;.;T;.;T;.;D;.;D
Polyphen		0.021	B;.;.;.;B;.;B;.;.;B;.;.;.;.
Vest4		0.45
MutPred		0.25		Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);.;Gain of helix (P = 0.027);.;.;.;.;Gain of helix (P = 0.027);.;Gain of helix (P = 0.027);.;Gain of helix (P = 0.027);
MVP		0.69
MPC		0.12
ClinPred		0.12	T
GERP RS		-0.096
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.18

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: chr17-41246793;