17-43079340-T-A

Position:

• chr17-43079340-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001407581.1(BRCA1):​c.4417A>T​(p.Ile1473Leu) variant causes a missense 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. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_001407581.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.110

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]

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

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043816894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4358-2726A>T		intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4358-2726A>T		intron_variant		1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

May 05, 2023

A variant of uncertain significance was detected in the BRCA1 gene (c.4417A>T). The p.Ile1473Leu variant located in coding exon 13 of the BRCA1 gene, results from a A to T substitution at nucleotide position 4417. The Isoleucine at codon 1473 is replaced by Leucine, This amino acid position is not conserved (PhyloP= 0.02 ). This variant not present in our local database nor was it identified in the Genome Aggregation Database The computational analyses (PolyPhen-2, SIFT, MutationTaster) do not suggest a high pathogenic impacts on the protein; however, this information is not predictive enough to rule out pathogenicity. ClinVar has an entry (371813) for another variant c.4417A>G at same postion with differnt aminoacid change p.Ile1473Val reported as uncertain significance . Since supporting evidence is limited at this time, this variant is classified as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.2
DANN	Benign	0.80
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	0.51	T
Vest4		0.15
MutPred		0.19		Loss of sheet (P = 0.0315);
MVP		0.085
MPC		0.080
ClinPred		0.060	T
GERP RS		-0.84
gMVP		0.042

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: chr17-41231357;