ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6323G>T (p.Arg2108Leu) (rs35029074)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168279 SCV000218951 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 2108 of the BRCA2 protein (p.Arg2108Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast cancer and prostate cancer (PMID: 29884136). This sequence change has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033) and the Universal Mutation Database (PMID: 22144684). However, in the individual reported in the Universal Mutation Database, a pathogenic allele was identified in the BRCA1 gene, which suggests that this c.6323G>T substitution in BRCA2 was not the primary cause of disease in this individual. ClinVar contains an entry for this variant (Variation ID: 91444). 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.
Ambry Genetics RCV000213911 SCV000273890 likely benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000423308 SCV000530979 likely benign not specified 2016-08-14 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000423308 SCV000919000 uncertain significance not specified 2020-12-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6323G>T (p.Arg2108Leu) results in a non-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 was absent in 245876 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6323G>T has been reported in the literature in individuals affected with breast cancer before 30, prostate cancer (Pajares_2018) and in a study of individuals with a personal and/or family history of BRCA-related cancers (Pirim_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA1 c.4065_4068delTCAA, p.Asn1355LysfsX10), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Health, Inc RCV000213911 SCV001353899 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-26 criteria provided, single submitter clinical testing This missense variant replaces arginine with leucine at codon 2108 of the BRCA2 protein. Computational prediction tool 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 individuals affected with breast cancer and prostate cancer (PMID: 29884136). A multifactorial likelihood analysis was inconclusive regarding the pathogenicity of this variant (PMID: 31131967). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285394 SCV001471813 uncertain significance none provided 2020-02-27 criteria provided, single submitter clinical testing The BRCA2 c.6323G>T; p.Arg2108Leu variant (rs35029074) is reported in the literature in individuals affected with breast or prostate cancer, but has also been identified in an individual with a pathogenic variant in BRCA1 (Pajares 2018). This variant is reported in ClinVar (Variation ID: 91444), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database). The arginine at codon 2108 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Arg2108Leu variant is uncertain at this time. References: Pajares B et al. Hereditary breast and ovarian cancer in Andalusian families: a genetic population study. BMC Cancer. 2018 Jun 8;18(1):647.
Sharing Clinical Reports Project (SCRP) RCV000076961 SCV000108758 likely benign Breast-ovarian cancer, familial 2 2012-03-08 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000076961 SCV000146826 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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