Submissions for variant NM_007294.4(BRCA1):c.5324T>G (p.Met1775Arg)

gnomAD frequency: 0.00001  dbSNP: rs41293463

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019264	SCV000244398	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	RCV000167787	SCV000076944	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1775 of the BRCA1 protein (p.Met1775Arg). This variant is present in population databases (rs41293463, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 7545954, 7939630, 22144684). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17694). 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: 12400015, 14534301, 19493677, 20516115, 23161852). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131375	SCV000186351	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-25	criteria provided, single submitter	clinical testing	The p.M1775R pathogenic mutation (also known as c.5324T>G), located in coding exon 19 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5324. The methionine at codon 1775 is replaced by arginine, an amino acid with similar properties. 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 10;562(7726):217-222). Numerous other functional studies have also found this variant to be deleterious (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee M et al. Hum. Mutat. 2012 Jan;33:22-8; Towler WI et al. Hum Mutat. 2013 Mar;34:439-45; Petitalot A et al. Mol Cancer Res. 2019 01;17:54-69). The p.M1775R alteration was also identified in a large, worldwide study of BRCA1/2 mutation-positive families (Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620). This alteration is located in the highly conserved BRCT repeat domain of BRCA1 and has been shown to have a severe impact on normal BRCA1 function/activity (Carvalho M et al. Cancer Res. 2007 Feb;67:1494-501; Nikolopoulos G et al. Biochim. Biophys. Acta. 2007 Jun;1774:772-80). Of note, this alteration is also designated as 5443T>G in some published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
GeneDx	RCV000048931	SCV000210213	pathogenic	not provided	2022-05-20	criteria provided, single submitter	clinical testing	Multifactorial studies suggest this variant is associated with hereditary breast and ovarian cancer (Lindor 2012); Published functional studies demonstrate a damaging effect: abolishes BRCA1 activity, including double strand break repair, transcription, and binding functions (Monteiro 1996, Kawai 2002, Williams 2003, Varma 2005, Towler 2013); Observed in many individuals with hereditary breast and ovarian cancer and has been reported as a recurrent variant in the African population (Futreal 1994, Miki 1994, Zhang 2012, Donenberg 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5443T>G; This variant is associated with the following publications: (PMID: 21666281, 19493677, 25782689, 17305420, 17308087, 16101277, 15133503, 15967981, 22739995, 26287763, 27495310, 23994874, 22646717, 21447777, 21520273, 8872468, 21922593, 18680205, 15235020, 7939630, 23161852, 12400015, 12427738, 16452482, 8942979, 20516115, 20737206, 11301010, 15133502, 17005433, 17063491, 1749388, 15689452, 16786532, 14729053, 20378548, 27469594, 7545954, 16528612, 27272900, 26681312, 28398198, 25085752, 29337092, 29106372, 28781887, 30209399, 29446198, 31343793, 33087888, 33087929, 30322717, 30765603, 31998812, 30787465, 33646313, 21990134)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000048931	SCV000296388	pathogenic	not provided	2019-11-27	criteria provided, single submitter	clinical testing	This variant has been reported in individuals and families affected with breast or ovarian cancer in the published literature (PMID: 7939630 (1994) and 7545954 (1994)). It has also been reported to be damaging to BRCA1 protein function (PMID: 23161852 (2013), 20516115 (2010), 19493677 (2009), 14534301 (2003), 12400015 (2002)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019264	SCV000326265	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131375	SCV000537680	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with arginine at codon 1775 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant impacts BRCA1 function in homology-directed DNA repair, transcription activation, haploid cell proliferation and protease sensitivity and protein-protein binding assays (PMID: 8942979, 9738006, 11301010, 12427738, 15689452, 23161852, 30209399). This variant has been reported as a recurring mutation and detected in multiple individuals affected with breast and/or ovarian cancer (PMID: 7837387, 7939630, 18284688, 19491284, 20104584, 24240112, 26287763, 27469594, 29337092, 34204722). This variant also has been reported to segregate with disease in a large pedigree with 24 cases of breast and ovarian cancer (PMID: 7545954). This variant has been identified in 4/282786 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Genologica Medica	RCV000019264	SCV000577939	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000019264	SCV000677661	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167787	SCV000699236	pathogenic	Hereditary breast ovarian cancer syndrome	2016-06-20	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5324T>G (p.Met1775Arg) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and hydrophobic Methionine (M) with a large size and basic Arginine (R) located in the BRCT domain. Consistently, 5/5 in silico tools predict a damaging outcome for this variant. The variant is absent in 124492 control chromosomes while it was reported in several HBOC patients including one family in which it was shown to co-segregate with the disease, indicating its pathogenicity. Moreover, functional studies demonstrated the variant to impair homology directed repair, single strand annealing, phosphopeptide-binding and transcriptional activity of BRCA1 further supporting a deleterious impact. Additionally, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170589	SCV001333177	pathogenic	Breast and/or ovarian cancer	2017-11-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000048931	SCV002050101	pathogenic	not provided	2021-01-20	criteria provided, single submitter	clinical testing	The BRCA1 c.5324T>G; p.Met1775Arg variant (rs41293463), also known as 5443T>G for traditional nomenclature, is reported in the literature in several individuals and families with hereditary breast and ovarian cancer syndrome (Carter 2018, Futreal 1994, Miki 1994), and shown to co-segregate with disease in at least one family (Miki 1994). Functional analyses of the variant protein show reduced protein stability and a severe impact on BRCA1 function (Caligo 2009, Fernandes 2019, Lee 2010, Towler 2013, Williams 2003). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 17694). This variant is found in the general population with an overall allele frequency of 0.001% (4/282786 alleles) in the Genome Aggregation Database. The methionine at codon 1775 is located in the highly conserved BRCT repeat domain of BRCA1, and computational analyses predict that this variant is deleterious (REVEL: 0.728). Based on available information, this variant is considered to be pathogenic. References: Caligo MA et al. A yeast recombination assay to characterize human BRCA1 missense variants of unknown pathological significance. Hum Mutat. 2009 Jan;30(1):123-33. Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. Fernandes VC et al. Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation. J Biol Chem. 2019 Apr 12;294(15):5980-5992. Futreal PA et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994 Oct 7;266(5182):120-2. 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. Miki Y et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66-71. Towler WI et al. Analysis of BRCA1 variants in double-strand break repair by homologous recombination and single-strand annealing. Hum Mutat. 2013 Mar;34(3):439-45. 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.
Baylor Genetics	RCV000019264	SCV004212713	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-16	criteria provided, single submitter	clinical testing
OMIM	RCV000019264	SCV000039552	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2006-04-07	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019264	SCV000053841	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019264	SCV000145453	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	RCV000167787	SCV000587495	pathogenic	Hereditary breast ovarian cancer syndrome	2015-12-17	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000048931	SCV000591612	pathogenic	not provided		no assertion criteria provided	clinical testing	The p.Met1775Arg variant was identified in the UMD 2X as a causal variant, in BIC 31X as a variant of unknown clinical importance, and also in the HGMD and LOVD databases. The variant was identified in dbSNP (ID#rs41293463) as a clinically associated SNP, with no population frequency data. In addition, this variant was not identified in 1000 control chromosomes from healthy individuals from one study (Phelan 2005), and was not reported in the Exome Variant Server ESP Project. This variant has been found to segregate with disease in one kindred (Miki 1994). The p.Met1775 residue is conserved across mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Met1775Arg variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Several functional studies have concluded that this variant has a deleterious effect on BRCA1 protein function. The mutation has been shown to inhibit the interaction of BRCA1 with the DNA helicase BACH1 (Clapperton 2004, Shiozaki 2004) and with the transcriptional corepressor CtIP (Varma 2005), and yeast and mammalian cell-based assays have demonstrated that the variant impairs transcription activation (Monteiro 1996, Phelan 2005, Tischkowitz 2008). One study utilized a proteolytic sensitivity assay which indicated that the variant results in a folding defect in the BRCT domains, and thus destabilization of this domain (Williams 2003). The authors of this study suggest that this abrogates BRCA1 function, and may explain the spectrum of defects observed in other studies. In summary, based on the above information, this variant is classified as pathogenic.
Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology	RCV000167787	SCV000916357	pathogenic	Hereditary breast ovarian cancer syndrome	2019-03-01	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000019264	SCV001238126	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro