rs80357007

chr17-43051107-C-Achr17-43051107-C-Gchr17-43051107-C-T

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.5288G>T(p.Gly1763Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1763A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 O:1
• 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 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 7 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, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5288G>T	p.Gly1763Val	missense_variant	20/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5288G>T	p.Gly1763Val	missense_variant	20/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461740 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	PS3(Strong)+PM2(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2023

The p.G1763V variant (also known as c.5288G>T), located in coding exon 19 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5288. The glycine at codon 1763 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in an individual who underwent BRCA1/2 testing through a commercial laboratory; however, the clinical history was not specified (Judkins T et al. Cancer Res. 2005 Nov 1;65(21):10096-103). Multiple functional assays assessing protein folding stability, phosphopeptide binding, and transcriptional activity showed compromised function (Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90). Another study that utilized bioinformatics analysis and a series of experiments investigating cell proliferation, cell cycle regulation, and chemotherapy response determined that this alteration did not affect the tumor suppressor function of BRCA1 (Zhang H et al. Oncol Lett, 2017 Nov;14:5839-5844). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM. et al. Nature 2018 10;562(7726):217-222). Based on internal structural analysis, G1763V is deleterious (Ambry internal data; Wu, Q et al. Mol Cell 2016 Feb;61(3):434-448). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 24, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2017

This variant is denoted BRCA1 c.5288G>T at the cDNA level, p.Gly1763Val (G1763V) at the protein level, and results in the change of a Glycine to a Valine (GGG>GTG). This variant has been identified in at least one individual with breast cancer (Judkins 2005). Functional studies have shown that this variant exhibits compromised phosphopeptide binding activity and specificity, mild protein folding defects, and reduced transcriptional activity compared to wild type (Lee 2010). BRCA1 Gly1763Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Gly1763Val occurs at a position that is conserved across species and is located in the BRCT 2 domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Gly1763Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2023

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial breast cancer (PMID: 29113215). ClinVar contains an entry for this variant (Variation ID: 55507). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 20516115, 29113215, 30209399). 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. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1763 of the BRCA1 protein (p.Gly1763Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.9	D;N;.;D;.;.;N;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D;.;D;.;.;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D
Polyphen		0.036, 1.0	.;B;.;.;.;D;.;.
Vest4		0.71
MVP		0.94
MPC		0.25
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.80

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: rs80357007; hg19: chr17-41203124;