ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4027A>G (p.Lys1343Glu)

dbSNP: rs483353114
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563477 SCV000661217 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-07 criteria provided, single submitter clinical testing The p.K1343E variant (also known as c.4027A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4027. The lysine at codon 1343 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in a patient with a history of thyroid adenoma and breast cancer (age 62), who developed possible therapy-related AML 2 years later. Family history included melanoma and cancer, primary site unknown (Schulz, E et al. J Med Genet. 2012 Jul;49(7):422-8). This amino acid position is not 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 RCV000820321 SCV000961029 uncertain significance Hereditary breast ovarian cancer syndrome 2020-10-20 criteria provided, single submitter clinical testing 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. 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 glutamic acid 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. This variant has been observed in an individual affected with breast cancer (PMID: 22652532). ClinVar contains an entry for this variant (Variation ID: 126034). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamic acid at codon 1343 of the BRCA2 protein (p.Lys1343Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid.
University of Washington Department of Laboratory Medicine, University of Washington RCV000563477 SCV003848617 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health RCV000113262 SCV004830010 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2023-08-23 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 1343 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been reported in an individual affected with therapy related myeloid neoplasm, however, the primary cancer of the carrier was not provided (PMID: 22652532) and in an individual who underwent hereditary cancer multigene panel testing (PMID: 31853058). This variant has not been identified 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113262 SCV000146358 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2012-04-07 no assertion criteria provided clinical testing

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