ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4189G>A (p.Glu1397Lys) (rs28897726)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203656 SCV000072383 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1397 of the BRCA2 protein (p.Glu1397Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual at risk for hereditary breast and ovarian cancer (PMID: 20127978). ClinVar contains an entry for this variant (Variation ID: 37887). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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.
GeneDx RCV000586214 SCV000210330 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4189G>A at the cDNA level, p.Glu1397Lys (E1397K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant, also known as BRCA2 4417G>A using alternate nomenclature, has been reported in at least one individual with familial breast cancer (Morgan 2010). BRCA2 Glu1397Lys was not observed in large population cohorts (Lek 2016). This variant is located within the POLH and RAD51 binding domains (Roy 2012, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Glu1397Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044370 SCV000600580 uncertain significance not specified 2016-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509937 SCV000607796 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000509937 SCV000688858 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586214 SCV000694750 uncertain significance not provided 2016-05-02 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4189G>A variant affects a conserved nucleotide, resulting in amino acid change from Glu to Lys. 2/3 in-silico tools predict this variant to be damaging (SNPs&GO and Mutation Taster not captured due to low statistical significance; SIFT had no prediction). This variant was not found in 120260 control chromosomes, but has been reported in breast cancer patients without evidence of causality (i.e. co-segregation). It has been observed to co-occur with a pathogenic BRCA2 c.4163_4164delCTinsA in at least 4 individuals (1 internal specimen, 3 BIC individuals, and 1 family from kConFab), suggesting that these two variants are in cis. The variant has also been reported to co-occur with another pathogenic BRCA2 variant, c.4169delT (Mattocks_BRCA1&2_Clin Chem_2010; phase not specified). Multiple clinical laboratories classified this variant as a VUS. Taken together, the variant was classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586214 SCV000889046 uncertain significance not provided 2017-11-03 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031468 SCV000054073 uncertain significance Breast-ovarian cancer, familial 2 2009-11-23 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031468 SCV000146390 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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