ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3458A>G (p.Lys1153Arg)

dbSNP: rs80358594
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044202 SCV000072215 uncertain significance Hereditary breast ovarian cancer syndrome 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1153 of the BRCA2 protein (p.Lys1153Arg). This variant is present in population databases (rs80358594, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 51471). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Ambry Genetics RCV000129509 SCV000184282 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-14 criteria provided, single submitter clinical testing The p.K1153R variant (also known as c.3458A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3458. The lysine at codon 1153 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002468997 SCV000694697 uncertain significance not specified 2022-11-11 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3458A>G (p.Lys1153Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250984 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3458A>G has been reported in the literature in at least one individual affected with lung adenocarcinoma (e.g. Lu_2015). These report(s) do not provide conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; 5 laboratories reported the variant as unknown significance, and one reported the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588905 SCV000887793 uncertain significance not provided 2020-11-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129509 SCV000903219 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-23 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 1153 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 been reported in a breast cancer case-control meta-analysis in 3/60463 cases and 2/53459 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007338) and a multifactorial analysis reported co-occurrence and family history likelihood ratios for pathogencity of 1.2148 and 0.508, respectively (PMID: 31131967). This variant has been identified in 3/250984 chromosomes 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.
GeneDx RCV000588905 SCV001783689 uncertain significance not provided 2020-09-02 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3686A>G; This variant is associated with the following publications: (PMID: 31131967)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000588905 SCV002047838 uncertain significance not provided 2020-11-08 criteria provided, single submitter clinical testing The BRCA2 c.3458A>G; p.Lys1153Arg variant (rs80358594), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 51471). This variant is found on only three chromosomes (3/250984 alleles) in the Genome Aggregation Database. The lysine at codon 1153 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.096). However, due to limited information, the clinical significance of the p.Lys1153Arg variant is uncertain at this time.
University of Washington Department of Laboratory Medicine, University of Washington RCV000129509 SCV003851978 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).
Breast Cancer Information Core (BIC) (BRCA2) RCV000113181 SCV000146240 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2004-02-20 no assertion criteria provided clinical testing

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