Submissions for variant NM_007294.4(BRCA1):c.5212G>A (p.Gly1738Arg)

dbSNP: rs80356937

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112566	SCV000244392	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	RCV000239131	SCV000076876	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1738 of the BRCA1 protein (p.Gly1738Arg). 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: 15353005, 16489001, 17453335, 17902052, 23536787, 24010542). It is commonly reported in individuals of Greek ancestry (PMID: 15353005, 17902052, 23536787). ClinVar contains an entry for this variant (Variation ID: 55461). 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 have shown that this missense change affects BRCA1 function (PMID: 17305420, 17308087, 18036263, 20516115). This variant disrupts the p.Gly1738 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10811118, 11157798, 18465347, 21918854, 23113073). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneKor MSA	RCV000239131	SCV000296779	pathogenic	Hereditary breast ovarian cancer syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This variation is a missense mutation, substituting Glycine with Arginine at codon 1738 of the BRCA1 protein p.(Gly1738Arg). The glycine residue is highly conserved among species and is located in a domain of the protein that is not known to be functionally important. There is a large physicochemical difference between glycine and arginine (Grantham Score 125). This variant is not present in population databases (rs80356937) and has been reported in international literature in breast and/or ovarian cancer patients and is a founder mutation in the Greek population (PMID: 17902052, PMID: 23536787, PMID: 15353005, PMID: 24010542, PMID: 17453335, PMID: 16489001). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging. In addition, experimental studies have shown that this missense variant is deleterious (PMID: 17305420, 18036263, 20516115, 17308087). A different missense substitution at this codon (p.Gly1738Glu) has been determined to be pathogenic (PMID: 18465347, PMID: 23113073, PMID: 21918854, PMID: 11157798, PMID: 10811118). This suggests that the glycine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112566	SCV000326218	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000112566	SCV000564322	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579604	SCV000683272	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1738 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 reported that this variant impacts BRCA1 function in transcription activation, haploid cell proliferation, yeast colony size, centrosome amplification, and radiation-induced nuclear foci assays (PMID: 14534301, 17308087, 18036263, 20516115, 27272900, 28781887, 30209399). This variant has been reported in dozens of individuals and families affected with breast and/or ovarian cancer (PMID: 12142080, 15353005, 17902052, 19491894, 22085629, 23536787, 29310832, 30340058, 30446274, 33274848) and is known as a founder mutation in the Greek population based on haplotype analysis (PMID: 17902052, 24010542). This variant has also been identified in 39 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). . This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different nucleotide change c.5212G>C resulting in the same protein consequence (ClinVar variation ID: 865165) and other missense substitutions at the same codon (p.Gly1738Glu, p.Gly1738Val) are known to be disease-causing in ClinVar (variation ID: 55462, 845528). This indicates the important role of glycine at this codon in BRCA1 function. Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985433	SCV001133617	pathogenic	not provided	2018-12-18	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/282860 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Appears to be associated with disease in multiple families.
Ambry Genetics	RCV000579604	SCV001185657	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-24	criteria provided, single submitter	clinical testing	The p.G1738R pathogenic mutation (also known as c.5212G>A), located in coding exon 18 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5212. The glycine at codon 1738 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21). This mutation is one of four Greek founder mutations which together account for 73% of mutations identified in BRCA1 in the Greek population (Anagnostopoulos T et al. Breast Cancer Res Treat. 2008;110(2):377-85). In two studies, this variant was identified in 0.4% to 3% of sporadic Greek breast and/or ovarian cancer families and in 3.7% to 12% of Greek carriers of a deleterious BRCA1 or BRCA2 mutation (Armaou S et al. Br J Cancer. 2009,7;101(1):32-7; Stavropoulou AV et al. PLoS One. 2013;8(3)). In addition, this alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). Multiple functional assays, including protease sensitivity, phosphopeptide binding activity, phosphopeptide binding specificity, and transcriptional assays have shown a deleterious effect (Karchin R et al. PLoS Comput. Biol. 2007;3(2):e26; Lovelock PK et al. Breast Cancer Res. 2007;9(6):R82); Carvalho MA et al. Cancer Res. 2007;15;67(4):1494-501; Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Thouvenot P et al. PLoS Genet. 2016 Jun 6;12(6):e1006096). In addition, one functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 Oct;562(7726):217-222). Of note, this variant may be referred to as G1738R (5331G>A) in some literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000239131	SCV001361730	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5212G>A (p.Gly1738Arg) results in a non-conservative amino acid change located in the BRCT linker domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found not found in 278112 control chromosomes (gnomAD). c.5212G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer where it co-segregated with the disease in over 8 families (e.g. Anagnostopoulos 2008, Konstantopoulou 2008, Chenevix-Trench 2006, Konstantopoulou 2014). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated severely diminished transcriptional activity, destabilization of the BRCT structure, reduced capacity to form foci in response to DNA damage, and increased centrosome amplification (Carvalho 2007, Lovelock 2007, Lee 2010, Thouvenot 2016, Findlay 2018). Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=8)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000985433	SCV001447130	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000579604	SCV002537826	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000985433	SCV003799626	pathogenic	not provided	2022-04-02	criteria provided, single submitter	clinical testing	The BRCA1 c.5212G>A; p.Gly1738Arg variant (rs80356937) is reported in the literature in several individuals with hereditary breast and ovarian cancer syndrome and shown to co-segregate with disease in multiple families (Anagnostopoulos 2008, Heramb 2018, Jakimovska 2018, Tsaousis 2019). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 55461). Functional studies show the variant causes altered protein function (Lee 2010, Lovelock 2007). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 1738 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.762). Based on available information, this variant is considered to be pathogenic. References: Anagnostopoulos T et al. G1738R is a BRCA1 founder mutation in Greek breast/ovarian cancer patients: evaluation of its pathogenicity and inferences on its genealogical history. Breast Cancer Res Treat. 2008 Jul;110(2):377-85. PMID: 17902052. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. PMID: 29339979. Jakimovska M et al. BRCA1 and BRCA2 germline variants in breast cancer patients from the Republic of Macedonia. Breast Cancer Res Treat. 2018 Apr;168(3):745-753. PMID: 29335924. 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. PMID: 20516115. Lovelock PK et al. Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants? Breast Cancer Res. 2007;9(6):R82. PMID: 18036263. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. PMID: 31159747.
Baylor Genetics	RCV000112566	SCV004216987	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-03-22	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112566	SCV000145396	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000239131	SCV000587480	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000112566	SCV001237926	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Center for Precision Medicine, Meizhou People's Hospital	RCV002250544	SCV002520878	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only