ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1096T>G (p.Leu366Val) (rs587779357)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000074510 SCV000108595 likely benign not specified 2016-07-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000166352 SCV000217140 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-08 criteria provided, single submitter clinical testing The p.L366V variant (also known as c.1096T>G), located in coding exon 9 of the BRCA2 gene, results from a T to G substitution at nucleotide position 1096. The leucine at codon 366 is replaced by valine, an amino acid with highly similar properties. This alteration was previously reported in a woman diagnosed with ovarian cancer at age 47 and was not associated with aberration in splicing based on RT-PCR (Thomassen M et al. Breast Cancer Res Treat. 2012 Apr;132:1009-23). This variant was also reported in 1/120 Brazilian breast cancer patients from HBOC families and was considered a variant of uncertain significance (Silva FC et al. BMC Med. Genet. 2014 May;15:55). 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.
Invitae RCV001087766 SCV000254167 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586794 SCV000600462 uncertain significance not provided 2020-01-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166352 SCV000683401 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-12 criteria provided, single submitter clinical testing This missense variant replaces leucine with valine at codon 366 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 15937982, 21120943, 21769658, 24884479). This variant has been identified in 7/249022 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000074510 SCV000694507 uncertain significance not specified 2021-06-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1096T>G (p.Leu366Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 2/5 splice prediction tools predict that this variant may create a novel 3' splicing acceptor site. However, one study showed that aberrant splicing was not found in a patient who carries this variant (Thomassen_2011). The variant allele was found at a frequency of 2.8e-05 in 249022 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1096T>G has been reported in the literature in individuals affected with breast and ovarian cancer (example, Velasco_2005, Thomassen_2011, Silva_2014, Caux-Montcoutier_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3 and VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000077249 SCV001138987 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077249 SCV000109046 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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