ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3458A>G (p.Lys1153Arg) (rs80358594)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129509 SCV000184282 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113181 SCV000146240 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000129509 SCV000903219 likely benign Hereditary cancer-predisposing syndrome 2015-11-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588905 SCV000694697 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3458A>G (p.Lys1153Arg) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121240 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant was reported in the BIC database in an individual who also carries pathogenic BRCA1 c.3607C>T, p.Arg1203Ter, suggesting the variant of interest was not the cause of disease in this patient. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000044202 SCV000072215 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-08 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1153 of the BRCA2 protein (p.Lys1153Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs80358594, ExAC 0.002%). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one individual, a pathogenic allele was identified in the BRCA1 gene, which suggests that this c.3458A>G substitution in BRCA2 was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 51471). 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588905 SCV000887793 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing

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