ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5348T>C (p.Met1783Thr) (rs55808233)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167822 SCV000076967 benign Hereditary breast and ovarian cancer syndrome 2020-11-25 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: 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 RCV000048954 SCV000209991 likely benign not specified 2018-02-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Pathway Genomics RCV000031240 SCV000223746 likely benign Breast-ovarian cancer, familial 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 and 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 Health, Inc 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 RCV000167822 SCV000839211 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000031240 SCV001140470 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031240 SCV000053844 benign Breast-ovarian cancer, familial 1 2009-08-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031240 SCV000145474 uncertain significance Breast-ovarian cancer, familial 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 1 no assertion provided in vitro

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