ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.440A>T (p.Gln147Leu) (rs80358674)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164577 SCV000215235 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000031481 SCV000785182 uncertain significance Breast-ovarian cancer, familial 2 2017-05-22 criteria provided, single submitter clinical testing
GeneDx RCV000589401 SCV000568903 uncertain significance not provided 2017-08-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.440A>T at the cDNA level, p.Gln147Leu (Q147L) at the protein level, and results in the change of a Glutamine to a Leucine (CAA>CTA). Using alternate nomenclature, this variant would be defined as BRCA2 668A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln147Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gln147Leu occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Gln147Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589401 SCV000694769 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.440A>T (p.Gln147Leu) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121006 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. 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.
Invitae RCV000816691 SCV000957209 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glutamine with leucine at codon 147 of the BRCA2 protein (p.Gln147Leu). The glutamine residue is weakly conserved and there is a moderate physicochemical difference between glutamine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Breast cancer (PMID:25186627). ClinVar contains an entry for this variant (Variation ID: 37900). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482889 SCV000600588 uncertain significance not specified 2016-12-17 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031481 SCV000054086 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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