Submissions for variant NM_007294.4(BRCA1):c.5348T>C (p.Met1783Thr)

gnomAD frequency: 0.00058  dbSNP: rs55808233

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167822	SCV000076967	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129758	SCV000184565	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000585920	SCV000209991	likely benign	not provided	2022-06-21	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Pathway Genomics	RCV000031240	SCV000223746	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-30	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000167822	SCV000267852	likely benign	Hereditary breast ovarian cancer syndrome	2016-04-25	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000414204	SCV000492489	uncertain significance	Breast neoplasm		criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000129758	SCV000683302	likely benign	Hereditary cancer-predisposing syndrome	2015-12-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000585920	SCV000699247	benign	not provided	2016-06-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5348C>T is a missense variant that changes a conserved T to C, resulting in an amino acid change from Met to Thr at codon 1783 in the C-terminal BRCT domain of BRCA1. This variant is predicted to be damaging by 5/5 in-silico tools. Functional studies indicate that the variant slightly reduces BRCA1 structural stability, has intermediate phosphopeptide-binding activity, reduced transcriptional activity, and 66% of wild type BRCA1 HDR function.This variant was found in 21/121366 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.001929 (20/10368). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Although this variant was reported in multiple patients in the literature and databases, lack of co-segregation (McKean Cowdin_HumGen_2005) and multiple co-occurrences with pathogenic variants (UMD database) were found in some of these patients/families. In addition, multiple reputable sources classify this variant as likely benign/benign. Taken together, this variant was scored as Benign.
Mendelics	RCV003492309	SCV001140470	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818195	SCV002066703	likely benign	not specified	2022-01-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000167822	SCV002504990	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000167822	SCV002515232	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000129758	SCV002537846	likely benign	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031240	SCV000053844	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2009-08-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031240	SCV000145474	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353920	SCV000591619	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Met1783Thr variant was identified in 2 of 838 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer and was not identified in 192 control chromosomes from healthy individuals (McKean-Cowdin 2005, Silva 2014). The variant was also identified in dbSNP (ID: rs55808233) as "With other allele", ClinVar (classified as benign by Invitae, Ambry Genetics, and two other submitters; as likely benign by GeneDx, Color, and two other submitters; and as uncertain significance by five submitters), LOVD 3.0 (15x), and UMD-LSDB (2x as likely neutral). In UMD, the variant was reported with a co-occurring, pathogenic BRCA1 variants c.755_761del (p.Arg252LeufsX44) and c.-200_80del (p.Met1SerfsX13), increasing the likelihood that the p.Met1783Thr variant does not have clinical significance. The variant was identified in control databases in 45 of 277188 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 41 of 24028 chromosomes (freq: 0.002, increasing the likelihood this could be a low frequency benign variant), Other in 2 of 6462 chromosomes (freq: 0.0003), and Latino in 2 of 34420 chromosomes (freq: 0.00006), while it was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. Although the p.Met1783 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the M variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. There are conflicting results in the literature regarding the effect of this variant on the BRCA1 protein, specifically within the BRCT domain where this variant is located. Functional studies demonstrated that the variant may be moderately destabilizing to the protein folding (Drikos 2009, Glover 2006, Williams 2003, Rowling 2010) but that protein binding capabilities of the mutant protein were similar to the wild type (Drikos 2009, Glover 2006) and that the mutant protein retains between 50-70% DNA repair activity relative to the wild type (Gaboriau 2015, Lu 2015). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735500	SCV000863638	uncertain significance	Breast and/or ovarian cancer	2013-10-07	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031240	SCV001238601	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro