Submissions for variant NM_007294.4(BRCA1):c.5363G>T (p.Gly1788Val)

gnomAD frequency: 0.00001  dbSNP: rs80357069

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031241	SCV000244400	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	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
Invitae	RCV000048961	SCV000076974	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-16	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000162885	SCV000213372	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-06	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000235698	SCV000292527	pathogenic	not provided	2021-11-08	criteria provided, single submitter	clinical testing	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)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031241	SCV000326293	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048961	SCV000699249	pathogenic	Hereditary breast ovarian cancer syndrome	2020-11-02	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000031241	SCV000785680	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-11-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235698	SCV000887726	pathogenic	not provided	2020-11-18	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002191	SCV001160062	pathogenic	not specified	2018-10-26	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000031241	SCV004216867	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-12-08	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031241	SCV000053845	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-09-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031241	SCV000145482	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031241	SCV001242679	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro