Submissions for variant NM_000059.4(BRCA2):c.343A>G (p.Lys115Glu)

gnomAD frequency: 0.00001  dbSNP: rs56242644

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129695	SCV000184496	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	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, susceptibility to, 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	2022-02-14	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. 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 Syndrome. Co-occurrence with one 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. Six ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129695	SCV000910974	likely benign	Hereditary cancer-predisposing syndrome	2016-05-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001367677	SCV001564034	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 115 of the BRCA2 protein (p.Lys115Glu). This variant is present in population databases (rs56242644, gnomAD 0.002%). This missense change has been observed in individual(s) with esophageal cancer and/or ovarian cancer (PMID: 12670525, 30128899). ClinVar contains an entry for this variant (Variation ID: 51463). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Sema4, Sema4	RCV000129695	SCV002533794	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-06	criteria provided, single submitter	curation
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113438	SCV000146624	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-11-25	no assertion criteria provided	clinical testing