ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4657T>A (p.Leu1553Met) (rs80357431)

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Total submissions: 6
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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 2020-01-17 criteria provided, single submitter clinical testing The p.L1553M variant (also known as c.4657T>A), located in coding exon 13 of the BRCA1 gene, results from a T to A substitution at nucleotide position 4657. The leucine at codon 1553 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000112375 SCV000785404 likely benign Breast-ovarian cancer, familial 1 2017-07-24 criteria provided, single submitter clinical testing
Invitae RCV001364498 SCV001560651 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-02-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 1553 of the BRCA1 protein (p.Leu1553Met). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs80357431, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 55254). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0. The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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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