17-43049164-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_007294.4(BRCA1):c.5363G>A(p.Gly1788Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,874 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1788V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:6 O:1
• Conservation: PhyloP100: 4.31

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 8 ACMG points.

• PM1: In a hotspot region, there are 6 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43049164-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 37660.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5363G>A	p.Gly1788Asp	missense_variant	21/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5363G>A	p.Gly1788Asp	missense_variant	21/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251442 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Uncertain significance, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Mar 25, 2019	To our knowledge this variant has only been seen alone once, in a male control in gnomAD (South Asian population). Clinical evidence in Goldgar et al 2004 (PMID: 15290653) is not applicable unless this variant is observed in cis with c.5359T>A (Variation ID 55548). We recommend that if c.5363G>A is detected in an individual, presence of c.5359T>A should be assessed. Functional assay data analysis of the c.5363G>A variant suggests that it is unlikely to alter protein function alone, but that it does alter function when in combination with BRCA1 c.5359T>A (PMID: 30765603; 30209399). For more information see the haplotype entry BRCA1 c.[5359T>A;5363G>A] (Variant ID 624568). -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 07, 2008	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 25, 2023	This missense variant replaces glycine with aspartic acid at codon 1788 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 reported this variant as normal compared to wild-type control in transcription activation, haploid cell proliferation, protein stability and peptide binding assays (PMID: 20516115, 21447777, 30209399). This variant has been reported in cis with BRCA1 p.Cys1887Ser in several individuals and families affected with breast and/or ovarian cancer (PMID: 16030099, 18284688, 23233716, 25628955 , 26543556, 28959512). This variant has been observed in cis with BRCA1 p.Cys1787Ser and cosegregated with disease (PMID: 15290653, 25628955). A multifactorial analysis reported a likelihood ratio for pathogenicity based on case-control data of 0.04567 (PMID: 31131967). Other missense variants this codon (ClinVar variation ID: 37660, 55550, 531438) and codon 1787 (ClinVar variation ID: 662455) are considered likely disease-causing, suggesting that glycine or similar amino acid at this codon is important for the protein function. This variant has been identified in 1/251442 chromosomes 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	Oct 19, 2022	The p.G1788D variant (also known as c.5363G>A), located in coding exon 20 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5363. The glycine at codon 1788 is replaced by aspartic acid, an amino acid with similar properties. One functional study found that this nucleotide substitution is functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Conversely, this variant had 25.03% of wildtype activity in a transcription activation assay (Woods NT et al. NPJ Genom Med, 2016 Mar;1:). Based on internal structural assessment G1788 alterations are expected to cause general structural disruption of the BRCT domain (Clapperton JA et al. Nat Struct Mol Biol, 2004 Jun;11:512-8). 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 conflicting at this time, the clinical significance of this alteration remains unclear. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 08, 2019

- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

research

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Jan 31, 2014

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control;reference population

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Jul 09, 2021

Data included in classification: Prevalence in cases vs controls is increased (PS4_sup) Absent from non-cancer females in gnomAD (PM2_mod). Critical residue within BRCT domain (PM1_mod). REVEL 0.862 (PP3_sup). Parsons et al, 2019 combined LR: 0.0457 (BP6_str). Data not included in classification: Conflicting functional data: Lee et al 2010 PMID: 20516115 = VUS Gaboriau et al 2015 PMID: 25748678 = 30-50% HR activity (VUS) Woods et al 2016 PMID: 28781887 = VUS Findlay et al 2018 PMID: 30209399 = FUNC (G1788V & G1788C both LOF), Bouwman et al 2020 PMID: 32546644 = Cisplatin NEUTRAL, Olaparib DEL, DR-GFP DEL G1788C and G1788V (class 5) also reported at this position (PM5 not applied due to conflicting functional data and PM1 already having been applied) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.6	D;N;.;.;.;.;N;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;.;.;D;.;.
Vest4		0.93
MVP		0.99
MPC		0.48
ClinPred		0.97	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.87

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: rs80357069; hg19: chr17-41201181;