17-43076512-T-C

Position:

• chr17-43076512-T-C

Variant summary

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

The ENST00000357654.9(BRCA1):​c.4460A>G​(p.Lys1487Arg) 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. 13/21 in silico tools predict a benign outcome for this variant. 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. K1487E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 ENST00000357654.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.62

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=0.10862422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4460A>G	p.Lys1487Arg	missense_variant	13/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4460A>G	p.Lys1487Arg	missense_variant	13/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 09, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2016	The p.K1487R variant (also known as c.4460A>G), located in coding exon 12 of the BRCA1 gene, results from an A to G substitution at nucleotide position 4460. The lysine at codon 1487 is replaced by arginine, an amino acid with highly similar properties. A functional evaluation of the transactivation activity of this alteration was inconclusive as this variant displayed ~50% of the wild type activity, which was considered the threshold for classification into deleterious or neutral (Carvalho M et al. Mutat. Res., 2009 Jan;660:1-11). This alteration has also been classified as likely to be neutral or of little clinical significance based on a classification system using interspecific sequence variation (Abkevich V et al. J. Med. Genet., 2004 Jul;41:492-507). Further, a computational study reported this alteration as a variant of uncertain significance based on data derived from an in vitro functional assay (Iversen ES et al. Cancer Epidemiol. Biomarkers Prev., 2011 Jun;20:1078-88). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 12, 2020

Variant summary: BRCA1 c.4460A>G (p.Lys1487Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251276 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4460A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Carvalho_2009, Azzollini_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in about 50-60% residual transactivation activity (Carvalho_2009), however based on these data, using a computational tool (VarCall) the variant was predicted to be likely not pathogenic (Woods_2016, Fernandes_2019). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27062684, 15235020, 18992264, 21447777, 30765603, 29884841) -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 10, 2022

ClinVar contains an entry for this variant (Variation ID: 55206). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 18992264, 21447777, 24845084, 30765603). 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 breast and/or ovarian cancer (PMID: 27062684, 32879886). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1487 of the BRCA1 protein (p.Lys1487Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;T;.;.;.;.;.;T;.;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.065	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	.;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N;N;.;N;N;N;N;N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.029	D;T;.;T;T;T;T;D;T;T
Sift4G	Benign	0.54	T;T;T;T;T;T;.;.;T;.
Polyphen		0.36, 0.61	.;B;.;.;.;.;.;P;.;.
Vest4		0.33
MVP		0.43
MPC		0.069
ClinPred		0.30	T
GERP RS		3.9
Varity_R		0.030
gMVP		0.090

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80357126; hg19: chr17-41228529;