ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5347A>C (p.Met1783Leu) (rs80357012)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048953 SCV000076966 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000220027 SCV000273843 likely benign Hereditary cancer-predisposing syndrome 2019-03-14 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Structural Evidence
Counsyl RCV000112627 SCV000488447 uncertain significance Breast-ovarian cancer, familial 1 2016-03-31 criteria provided, single submitter clinical testing
GeneDx RCV000590089 SCV000570047 uncertain significance not provided 2016-12-16 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5347A>C at the cDNA level, p.Met1783Leu (M1783L) at the protein level, and results in the change of a Methionine to a Leucine (ATG>CTG). Using alternate nomenclature, this variant would be defined as BRCA1 5466A>C. This variant was observed in at least one individual with diffuse large B-cell lymphoma (Björkman 2015), and functional studies have suggested no impact on BRCA1 function with respect to stability, transcription, and homology-directed repair when compared to wild type (Lee 2010, Lu 2015). BRCA1 Met1783Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Met1783Leu occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located within the BRCT 2 domain and a region known to interact with multiple proteins (Paul 2014, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Met1783Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000048953 SCV000586910 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590089 SCV000699246 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5347A>C (p.Met1783Leu) variant involves the alteration of a conserved nucleotide. It is located in BRCT domain of the protein (InterPro). 2/4 in silico tools predict a benign outcome for this substitution. This variant was found in 3/121156 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant was only found in East Asian cohort with an allele frequency of 3/8650, thus it may be a rare polymorphism in East Asians. It was reported in at least one individual from an HBOC family (Judkins_2005) and in a lymphoma patient (Bjorkman_2015), however without strong evidence for causality such as co-segregation. Functional studies have demonstrated that the variant not to have any impact on HDR, transcription activation, phosphopeptide binding activity and protein stability of BRCA1 protein suggesting for neutrality (Lee_2008, Lu_2015). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance without evidence to independently evaluate. Taken together, this variant is currently classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590089 SCV000887725 uncertain significance not provided 2017-09-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000220027 SCV000903153 likely benign Hereditary cancer-predisposing syndrome 2016-07-18 criteria provided, single submitter clinical testing
Breast Center,Key Laboratory of Carcinogenesis and Translational Research RCV000048953 SCV001430341 benign Hereditary breast and ovarian cancer syndrome 2020-05-01 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112627 SCV000145473 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 RCV000112627 SCV000591618 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Met1783Leu variant has not been identified in affected individuals in the literature, but has been identified in the LOVD database, and in the BIC database 2x as a variant of unknown clinical importance. The p.Met1783 residue is not conserved in mammals and the variant amino acid Leucine is present in purple sea urchin, increasing the likelihood this variant does not have clinical significance. Computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. Two other amino acid changes at this position, p.Met1783Thr and p.Meth1483Ala were suggested to be deleterious by functional assays and predictive in silico analyses (Coyne 2004, Karchin 2007, Miyake 2000, Zhang 1998), increasing the likelihood that a change at this position is significant. However, one functional study for the variant p.Met1783Leu suggested that this specific change had no functional effect (Lee 2010), while an in silico study using functional data predicted this variant to be of unknown significance (Iversen 2011). In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. Therefore, this variant is classified as a variant of unknown significance.
Brotman Baty Institute,University of Washington RCV000112627 SCV001238211 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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