rs80357069

chr17-43049164-C-Achr17-43049164-C-Gchr17-43049164-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):c.5363G>T(p.Gly1788Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,166 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1788D) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12 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 Pathogenic. Variant got 18 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 chr17-43049165-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 17-43049164-C-A is Pathogenic according to our data. 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. Variant chr17-43049164-C-A is described in Lovd as [Pathogenic]. Variant chr17-43049164-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5363G>T	p.Gly1788Val	missense_variant	21/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5363G>T	p.Gly1788Val	missense_variant	21/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251442 Hom.: 0 AF XY: 0.00 AC XY: 0 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6 Other:1

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 07, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 08, 2022	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2021	Published functional studies demonstrate a damaging effect: disrupted protein stability, decreased transcriptional activation, and defective homology directed repair (Williams 2003, Gaiser 2004, Williams 2004, Phelan 2005, Glover 2006, Lee 2010, Rowling 2010, Lu 2015, Findlay 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history of breast or ovarian cancer (Berchuck 1998, Chen 2009, Cao 2013, Kanchi 2014, Lu 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Also known as 5482G>T; This variant is associated with the following publications: (PMID: 15004537, 15133503, 10946236, 20081198, 23318652, 24448499, 18418466, 17924331, 9796975, 15235020, 17305420, 21447777, 20378548, 20516115, 15609993, 18951461, 18512148, 15172985, 14534301, 16528612, 22753008, 18992264, 12096901, 20423312, 26848529, 15689452, 26689913, 26787237, 27272900, 26187060, 28724667, 28781887, 30702160, 29446198, 30730459, 30765603, 29625052, 33087888, 31825140, 34063805, 21990134, 30209399) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 18, 2020	This variant has been reported in individuals with breast and/or ovarian in the published literature (PMID: 29446198 (2018), 28724667 (2017), 26689913 (2015), 23318652 (2013), 21990134 (2012), 21614564 (2012), 21447777 (2011), 18512148 (2009), 12354934 (2002), 9796975 (1998)). Functional studies indicate that this variant has a damaging impact on the BRCA1 protein (PMID: 30209399 (2018), 27272900 (2016), 20516115 (2010), 18992264 (2009), 14534301 (2003)). This variant is located in potentially critical domain of the protein (BRCT domain) and other pathogenic or likely pathogenic variants affect the same amino acid. Therefore, the variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 16, 2023	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1788 of the BRCA1 protein (p.Gly1788Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9796975, 16267036, 18512148, 21614564, 26689913). It has also been observed to segregate with disease in related individuals. This variant is also known as 5482G>T. ClinVar contains an entry for this variant (Variation ID: 37660). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 14534301, 15689452, 20516115, 26689913). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 02, 2020	Variant summary: BRCA1 c.5363G>T (p.Gly1788Val) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 252442 control chromosomes. c.5363G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of BRCA1 protein structural stability, peptide binding specificity, and transcriptional activity (example, Williams_2003, Phelan_2005, Lee_2010, Rowling_2010, Coyne_2004). Seven clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 26, 2018

The BRCA1 c.5363G>T; p.Gly1788Val variant (rs80357069) is reported in the literature in multiple individuals affected with breast or ovarian cancer (Berchuck 1998, Chen 2009, Easton 2007, Kwong 2015, Lu 2015, Sun 2017, Zhang 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37660), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 1788 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show protease sensitivity, impaired protein folding, and reduced stability, homologous recombination activity, and transcriptional activity (Lee 2010, Lu 2015, Phelan 2005, Williams 2003). Based on available information, the p.Gly1788Val variant is considered to be pathogenic. References: Berchuck A et al. Frequency of germline and somatic BRCA1 mutations in ovarian cancer. Clin Cancer Res. 1998 Oct;4(10):2433-7. Chen W et al. BRCA1 germline mutations and tumor characteristics in Chinese women with familial or early-onset breast cancer. Breast Cancer Res Treat. 2009 Sep;117(1):55-60. Easton DF et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007 Nov;81(5):873-83. Kwong A et al. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries. J Med Genet. 2016 Jan;53(1):15-23. Lee MS et al. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res. 2010 Jun 15;70(12):4880-90. Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. Phelan CM et al. Classification of BRCA1 missense variants of unknown clinical significance. J Med Genet. 2005 Feb;42(2):138-46. Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. Williams RS et al. Detection of protein folding defects caused by BRCA1-BRCT truncation and missense mutations. J Biol Chem. 2003 Dec 26;278(52):53007-16. Zhang J et al. Prevalence and characterization of BRCA1 and BRCA2 germline mutations in Chinese women with familial breast cancer. Breast Cancer Res Treat. 2012 Apr;132(2):421-8. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

The p.G1788V pathogenic mutation (also known as c.5363G>T), located in coding exon 20 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5363. The glycine at codon 1788 is replaced by valine, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals with a personal and family histories of breast and/or ovarian cancer (Berchuck A et al. Clin Cancer Res. 1998 Oct;4(10):2433-7; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Cao W et al. J Epidemiol 2013 Jan;23(2):75-84; Rebbeck T et al. Hum. Mutat. 2018 May;39(5):593-620). In a series of functional analyses, this alteration was determined to result in a severe protein folding defect, binding specificity of less than 20% of wild type (but normal binding activity), and transcriptional activity of less than 20% of wild type (Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90). Other functional studies have also demonstrated that this alteration leads to significant loss of function (Woods et al. NPJ Genom Med 2016 Mar;1; Findlay GM et al. Nature 2018 10;562(7726):217-222). Based on internal structural assessment, alterations at codon 1788 are expected to cause general structural disruption of the BRCT domain (Clapperton, JA et al. Nat. Struct. Mol. Biol. 2004 Jun;11(6):512-8). Of note, this alteration is also referred to as 5482G>T in published literature. 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 available evidence, this alteration is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	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	0.52	T
PROVEAN	Pathogenic	-6.9	D;N;.;.;.;.;N;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		0.30, 1.0	.;B;.;.;.;D;.;.
Vest4		0.98
MVP		0.97
MPC		0.49
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.92

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; COSMIC: COSV58788398;