ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.343A>G (p.Lys115Glu) (rs56242644)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129695 SCV000184496 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-05 criteria provided, single submitter clinical testing The p.K115E variant (also known as c.343A>G), located in coding exon 3 of the BRCA2 gene, results from an A to G substitution at nucleotide position 343. The lysine at codon 115 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in a patient with high-grade serous ovarian cancer (Marchetti C et al, 2018 Nov;25:3701-3708). This alteration has been reported in a Chinese patient diagnosed with esophageal squamous cell carcinoma (Hu N et al. Cancer Detect. Prev. 2003;27(2):132-8). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al, 2018 04;14:e1007352). This alteration was classified as likely benign based on a multifactorial analysis model of variant classification (Parsons MT et al, 2019 09;40:1557-1578). 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.
GeneDx RCV000586594 SCV000210233 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.343A>G at the cDNA level, p.Lys115Glu (K115E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). Using alternate nomenclature, this variant would be defined as BRCA2 571A>G. This variant has been observed in an individual with ovarian cancer and in at least one other individual evaluated for cancer predisposition (Cheng 2017, Marchetti 2018). BRCA2 Lys115Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Lys115Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000113438 SCV000488710 uncertain significance Breast-ovarian cancer, familial 2 2016-05-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000235137 SCV000602793 uncertain significance not specified 2016-09-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235137 SCV000694696 uncertain significance not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.343A>G (p.Lys115Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251004 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.343A>G, has been reported in the literature in individuals affected with esophageal and ovarian cancer (Hu_2003, Marchetti_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.3869_3870delAA , p.Lys1290fsX4), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4x VUS, 1x likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV000129695 SCV000910974 likely benign Hereditary cancer-predisposing syndrome 2016-05-29 criteria provided, single submitter clinical testing
Invitae RCV001367677 SCV001564034 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-10 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 115 of the BRCA2 protein (p.Lys115Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with esophageal cancer and ovarian cancer (PMID: 12670525, 30128899). ClinVar contains an entry for this variant (Variation ID: 51463). 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113438 SCV000146624 uncertain significance Breast-ovarian cancer, familial 2 2004-11-25 no assertion criteria provided clinical testing

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