ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4657T>A (p.Leu1553Met) (rs80357431)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212184 SCV000210183 uncertain significance not provided 2015-07-10 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4657T>A at the cDNA level, p.Leu1553Met (L1553M) at the protein level, and results in the change of a Leucine to a Methionine (TTG>ATG). Using alternate nomenclature, this variant would be defined as BRCA1 4776T>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Leu1553Met 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 Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Leu1553Met occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is not located in a known functional domain (UniProt). While published in silico and evolutionary conservation analysis predicted that this variant is probably damaging (Pavlicek 2004), in-house in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Leu1553Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000164710 SCV000215379 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000112375 SCV000785404 likely benign Breast-ovarian cancer, familial 1 2017-07-24 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112375 SCV000145142 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112375 SCV000297614 uncertain significance Breast-ovarian cancer, familial 1 2009-05-08 no assertion criteria provided clinical testing

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