ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4873G>A (p.Glu1625Lys) (rs587782754)

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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 RCV000132268 SCV000187351 uncertain significance Hereditary cancer-predisposing syndrome 2015-10-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
GeneDx RCV000215379 SCV000278854 uncertain significance not provided 2017-07-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4873G>A at the cDNA level, p.Glu1625Lys (E1625K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 5101G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu1625Lys was observed at an allele frequency of 0.03% (5/16454) in individuals of South Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu1625Lys occurs at a position that is not conserved and is located in the POLH and RAD51 binding domains (Roy 2012, Buisson 2014). 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 Glu1625Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000468942 SCV000549736 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1625 of the BRCA2 protein (p.Glu1625Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs587782754, ExAC 0.03%) but has not been reported in the literature in individuals with a BRCA2-related disease. This variant has been observed in an individual with BRCA2-related disease (Invitae database). However, in that individual, a pathogenic allele was also identified in a different gene, which suggests that this c.4873G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 142833). 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 lysine 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.
Counsyl RCV000144218 SCV000785080 uncertain significance Breast-ovarian cancer, familial 2 2017-04-06 criteria provided, single submitter clinical testing
Color RCV000132268 SCV000911716 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-26 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000144218 SCV000189307 uncertain significance Breast-ovarian cancer, familial 2 2011-02-17 no assertion criteria provided clinical testing

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