ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1409A>C (p.Glu470Ala) (rs750341436)

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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 RCV000220996 SCV000278360 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-13 criteria provided, single submitter clinical testing
Color RCV000220996 SCV000683422 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000499995 SCV000591743 uncertain significance not specified 2015-06-10 criteria provided, single submitter clinical testing
GeneDx RCV000657040 SCV000617104 uncertain significance not provided 2017-11-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1409A>C at the cDNA level, p.Glu470Ala (E470A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). Using alternate nomenclature, this variant would be defined as BRCA2 1637A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu470Ala was not observed at a significant frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu470Ala is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Glu470Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000757932 SCV000953462 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 470 of the BRCA2 protein (p.Glu470Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs750341436, ExAC 0.002%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 233895). 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 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000757932 SCV000886458 benign Hereditary breast and ovarian cancer syndrome 2018-09-28 criteria provided, single submitter research The BRCA2 variant designated as NM_000059.3(BRCA2):c.1409A>C (p.Glu470Ala) is classified as benign. Computer software programs predict that this variant is likely to be tolerated, adding supporting evidence that this variant is benign. This variant is found in exon 10, in a domain where non-truncating mutations are usually benign. Co-segregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and demonstrates that this allele has a likelihood ratio of pathogenicity of 0.0004 to 1 (Thompson et al, 2003, PMID:2900794), providing additional evidence that this variant is less likely to cause cancer. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of benign. This variant is not predicted to alter BRCA2 function or modify cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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