ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3970A>T (p.Met1324Leu) (rs587782241)

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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 RCV000130943 SCV000185856 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
Invitae RCV000460345 SCV000549304 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-03 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 1324 of the BRCA1 protein (p.Met1324Leu). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 142109). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508593 SCV000605862 uncertain significance not specified 2016-12-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588718 SCV000699091 uncertain significance not provided 2016-11-25 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3970A>T (p.Met1324Leu) variant causes a missense change involving a non-conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications. A clinical diagnostic laboratory via ClinVar reports the variant as "uncertain significance." Because of the absence of clinical information and the lack of functional studies, the variant is classified as a Variant of Uncertain Significance (VUS), until additional information becomes available.
Counsyl RCV000663100 SCV000786210 uncertain significance Breast-ovarian cancer, familial 1 2018-03-22 criteria provided, single submitter clinical testing
Color RCV000130943 SCV000911782 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing

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