ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5509T>C (p.Trp1837Arg) (rs80356959)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129546 SCV000184326 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA1) RCV000031260 SCV000145556 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000129546 SCV000908978 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing
Counsyl RCV000031260 SCV000785711 likely pathogenic Breast-ovarian cancer, familial 1 2017-11-07 criteria provided, single submitter clinical testing
GeneDx RCV000236322 SCV000292710 likely pathogenic not provided 2017-01-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5509T>C at the cDNA level, p.Trp1837Arg (W1837R) at the protein level, and results in the change of a Tryptophan to an Arginine (TGG>CGG). Using alternate nomenclature, this variant has been previously published as BRCA1 5628T>C. This variant has been observed in at least three individuals with a personal and/or family history of early-onset breast cancer (Montagna 1996, Meindl 2002, Phelan 2005). Segregation analysis was performed in the kindred reported by Phelan et al. (2005); however, an insufficient number of individuals were tested to draw definitive conclusions regarding this variantÂ’s interpretation. Functional analyses have consistently found BRCA1 Trp1837Arg to decrease transactivation activity and destabilize the BRCA1 protein, supporting a deleterious effect (Williams 2003, Phelan 2005, Lee 2010, Rowling 2010). BRCA1 Trp1837Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tryptophan and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Trp1837Arg occurs at a position that is conserved through mammals and is located within the BRCT 2 domain as well as a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider BRCA1 Trp1837Arg to be a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000779893 SCV000916785 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5509T>C (p.Trp1837Arg) variant involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a deleterious outcome. Multiple functional studies from different model systems showed mutant protein with decreased stability and solubility, compromised substrate binding activity, increased protease sensitivity, decreased transcription activation level, and increased cisplatin sensitivity (Phelan_2005, Bouwman_2013, Williams_2003, Lee_ 2010, and Rowling _2010), suggesting a defective function of the protein associated with this variant. Structural 3-D modeling study and comparative sequence alignment studies predicted the variant to be cancer-associated or likely to be deleterious (Mirkovic_2004 and Abkevich _2004, respectively). This variant is absent in 242136 control chromosomes in gnomAD. This variant was found in many families with or at risk of HBOC (Montagna _1996, Meisel_2017, Fernandes_2016, Zanella_2017, Azzollini_2016, Park_2017). However, in one family the variant was identified in a father with prostate cancer and in his daughter who had breast cancer at age 39 but it was absent in two cousins of the proband affected with breast and bladder cancer (Phelan_2005), indicating lack of co-segregation of the variant with the disease or another pathogenic variant may present in this family. Phelan_2005 stated that this variant has not been observed to co-occur with a known deleterious BRCA1 mutation in 40000 samples from Myriad genetics Lab. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic (without evidence to independently evaluate). Taken together, this variant is classified as likely pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031260 SCV000053864 likely pathogenic Breast-ovarian cancer, familial 1 2010-11-17 no assertion criteria provided clinical testing

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