17-43047687-A-G

Position:

• chr17-43047687-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_007294.4(BRCA1):​c.5423T>C​(p.Val1808Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. V1808L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 O:1
• Conservation: PhyloP100: 4.87

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5423T>C	p.Val1808Ala	missense_variant	22/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5423T>C	p.Val1808Ala	missense_variant	22/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 30, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 15, 1997	- -
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 this sample . This sequence change replaces valine with alanine at codon 1829 of the BRCA1 protein (p.Val1829Ala ) also known as c.5486T>C, which located in coding exon 23 of the BRCA1 gene(NM_007300.3), results from a T to C substitution at nucleotide position 5486. This amino acid position is highly conserved. This variant is not present in population databases (gnomAD ). This variant reported in ClinVar database (ID: 55572) . This alteration is predicted to be possibly damaging and deleterious by ( BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationTaster and SIFT). The inviro function test shows intermediate function in a haploid cell survival assay (PMID: 30209399). Additional analysis shows uncertain functionality in terms of transcriptional activation and protein binding (PMID: 20516115). 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. -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 26, 2023	The p.V1808A variant (also known as c.5423T>C), located in coding exon 21 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5423. The valine at codon 1808 is replaced by alanine, an amino acid with similar properties. This alteration shows intermediate function in a haploid cell survival assay as well as a yeast small colony phenotype assay (Findlay GM et al. Nature, 2018 10;562:217-222; Coyne RS et al. Cancer Biol. Ther., 2004 May;3:453-7). Additional analysis shows no defect in protein folding, and uncertain functionality in terms of transcriptional activation, and protein binding (Lee MS et al. Cancer Res. 2010 Jun;70:4880-90). Several computational methods predict this alteration has at lease a moderate destabilizing effect on the protein (Rowling PJ et al. J. Biol. Chem., 2010 Jun;285:20080-7; Mirkovic N et al. Cancer Res., 2004 Jun;64:3790-7; Williams RS et al. J. Biol. Chem., 2003 Dec;278:53007-16). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2022	This missense variant replaces valine with alanine at codon 1808 in the BRCT domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in a moderately destabilized BRCA1 protein with a larger proportion of unfolded protein at physiological conditions in comparison to the wild type protein (PMID 20378548), and an intermediate function score (PMID 30209399). However, functional studies have also shown that the BRCA1 V1808A protein has proteolytic stability indistinguishable from the WT protein (PMID20516115). Functional studies in yeast have shown this variant causes a small colony phenotype, predictive of a negative impact on BRCA1 structure or function (PMID 15004537). 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 13, 2021

This sequence change replaces valine with alanine at codon 1808 of the BRCA1 protein (p.Val1808Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with BRCA1-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 55572). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 14534301, 15004537, 20378548, 20516115). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;T;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	D;N;.;.;.;.;N;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;D;.;.;.;.;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D
Polyphen		0.064, 1.0	.;B;.;.;.;D;.;.
Vest4		0.87
MVP		0.99
MPC		0.34
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80357358; hg19: chr17-41199704;