chr17-43071166-C-T

Position:

• chr17-43071166-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007294.4(BRCA1):​c.4748G>A​(p.Arg1583Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.00200

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.118070096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4748G>A	p.Arg1583Lys	missense_variant	15/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4748G>A	p.Arg1583Lys	missense_variant	15/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251362 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

-

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2018

The p.R1583K variant (also known as c.4748G>A and 4876G>A), located in coding exon 14 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4748. The arginine at codon 1583 is replaced by lysine, an amino acid with highly similar properties. This alteration has been reported in a Taiwanese individual with ovarian cancer (Chao A et al. Oncotarget 2016 Dec;7(51):85529-85541). Based on protein sequence alignment, this amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 25, 2023

ClinVar contains an entry for this variant (Variation ID: 230482). 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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 32546644). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. This missense change has been observed in individual(s) with ovarian cancer (PMID: 27907908). This variant is present in population databases (rs752624544, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1583 of the BRCA1 protein (p.Arg1583Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	5.4
DANN	Benign	0.50
DEOGEN2	Benign	0.097	.;T;.;.;T;.;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.67	T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.1	.;L;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.92	N;N;.;N;.;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.42	T;T;.;T;.;T;T;T;T;T
Sift4G	Benign	0.78	T;T;T;T;T;T;T;.;.;T
Polyphen		0.037, 0.0010	.;B;.;.;.;.;.;.;B;.
Vest4		0.27
MVP		0.49
MPC		0.084
ClinPred		0.0092	T
GERP RS		-1.5
Varity_R		0.023
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

LitVar

Other links and lift over

dbSNP: rs752624544; hg19: chr17-41223183; COSMIC: COSV105897732; COSMIC: COSV105897732;