ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3247A>C (p.Met1083Leu) (rs397507213)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164913 SCV000215601 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000559848 SCV000635890 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 1083 of the BRCA1 protein (p.Met1083Leu). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs397507213, ExAC 0.003%). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 18092194, 25186627). ClinVar contains an entry for this variant (Variation ID: 37517). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine 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.
Integrated Genetics/Laboratory Corporation of America RCV000590619 SCV000699009 uncertain significance not provided 2016-10-03 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3247A>C (p.Met1083Leu) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). Met1083 is not conserved across species and is not located in a known functional domain.This variant was found in 2/121344 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl RCV000031098 SCV000784960 uncertain significance Breast-ovarian cancer, familial 1 2017-02-22 criteria provided, single submitter clinical testing
Color RCV000164913 SCV000909313 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-06 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031098 SCV000053694 uncertain significance Breast-ovarian cancer, familial 1 2009-06-16 no assertion criteria provided clinical testing

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