chr17-43076614-G-C

Variant names:

• chr17-43076614-G-C
• NM_007294.4:c.4358C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_007294.4(BRCA1):​c.4358C>G​(p.Ala1453Gly) 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. 14/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 5 ACMG points.

• PM1: In a compositionally_biased_region Polar residues (size 28) in uniprot entity BRCA1_HUMAN there are 12 pathogenic changes around while only 5 benign (71%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4358C>G	p.Ala1453Gly	missense_variant, splice_region_variant	Exon 13 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4358C>G	p.Ala1453Gly	missense_variant, splice_region_variant	Exon 13 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A1453G variant (also known as c.4358C>G) is located in coding exon 12 of the BRCA1 gene. The alanine at codon 1453 is replaced by glycine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 12. This amino acid position is not well conserved in available vertebrate species. As a missense variant, this alteration is predicted to be tolerated by in silico analysis. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.00012	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.098	.;T;.;.;T;.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.75	T;T;T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.066	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;L;.;.;.;.;.
PROVEAN	Benign	-0.36	N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.30	T;T;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;.;.;T;.
Polyphen		0.094, 0.0040	.;B;.;.;B;.;.
Vest4		0.27
MutPred		0.13		.;Gain of sheet (P = 0.0827);.;.;.;.;.;
MVP		0.43
ClinPred		0.079	T
GERP RS		1.7
Varity_R		0.032

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.79		Position offset: -3

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: chr17-41228631;