rs1555581794

Positions:

• chr17-43074334-G-C

Variant summary

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

The NM_007294.4(BRCA1):​c.4672C>G​(p.Leu1558Val) 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. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L1558L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.32

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4672C>G	p.Leu1558Val	missense_variant	14/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4672C>G	p.Leu1558Val	missense_variant	14/23	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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 13, 2020	This missense variant replaces leucine with valine at codon 1558 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2024	The p.L1558V variant (also known as c.4672C>G), located in coding exon 13 of the BRCA1 gene, results from a C to G substitution at nucleotide position 4672. The leucine at codon 1558 is replaced by valine, an amino acid with highly similar properties. This variant was reported as a germline alteration in an individual with prostate cancer who underwent whole genome sequencing of tumor tissue (White JA et al. Cancer Res Commun. 2022 Sep;2(9):1005-1016). This variant was also reported in an individual with ovarian cancer who had negative tumor HRD testing (Guarischi-Sousa R. Diagnostics (Basel) 2023 Oct;13(21). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for the missense impact of this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 11, 2021

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2023

ClinVar contains an entry for this variant (Variation ID: 479263). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1558 of the BRCA1 protein (p.Leu1558Val). 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. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;T;.;.;T;.;.;.;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.68	T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.8	.;L;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.0	N;N;.;N;.;N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.14	T;D;.;T;.;D;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T;T;T;.;.;T
Polyphen		0.41, 0.78	.;B;.;.;.;.;.;.;P;.
Vest4		0.26
MVP		0.79
MPC		0.083
ClinPred		0.22	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.92		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555581794; hg19: chr17-41226351;