rs1171055085

chr17-43076614-G-Achr17-43076614-G-Cchr17-43076614-G-T

Variant summary

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

The NM_007294.4(BRCA1):c.4358C>T(p.Ala1453Val) variant causes a missense, splice region 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. 13/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1453E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.5028
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.412

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=0.11908427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4358C>T	p.Ala1453Val	missense_variant, splice_region_variant	13/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4358C>T	p.Ala1453Val	missense_variant, splice_region_variant	13/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 30, 2023	The p.A1453V variant (also known as c.4358C>T) is located in coding exon 12 of the BRCA1 gene. The alanine at codon 1453 is replaced by valine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 12. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1453 of the BRCA1 protein (p.Ala1453Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 481452). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.81	T;T;T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N;N;N;N
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0060	D;D;D;D;D;D;D
Sift4G	Benign	0.14	T;T;T;.;.;T;.
Polyphen		0.0, 0.95	.;B;.;.;P;.;.
Vest4		0.26
MutPred		0.15		.;Gain of methylation at K1452 (P = 0.0372);.;.;.;.;.;
MVP		0.50
ClinPred		0.54	D
GERP RS		1.7
Varity_R		0.067

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.50
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1171055085; hg19: chr17-41228631;