ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7006C>T (p.Arg2336Cys) (rs431825347)

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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 RCV000132214 SCV000187296 likely benign Hereditary cancer-predisposing syndrome 2018-03-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Other data supporting benign classification
Michigan Medical Genetics Laboratories,University of Michigan RCV000082966 SCV000196000 uncertain significance Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000588307 SCV000210410 uncertain significance not provided 2018-06-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7006C>T at the cDNA level, p.Arg2336Cys (R2336C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant, also defined as BRCA2 7234C>T using alternate nomenclature, has been observed in at least two individuals with a personal and/or family history of breast and/or ovarian cancer (Levanat 2012, Alemar 2017). BRCA2 Arg2336Cys 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 Arg2336Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000476201 SCV000549540 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2336 of the BRCA2 protein (p.Arg2336Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs431825347, ExAC no frequency). This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 22366370, Invitae). However, in one of these individuals a pathogenic allele were also identified in BRCA2, which suggests that this c.7006C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 96845). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The cysteine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. Several different missense substitutions at this codon (p.Arg2336Pro, p.Arg2336Leu, p.Arg2336His) have been determined to be pathogenic, primarily due to effects on mRNA splicing (PMID: 16792514, 22505045). However, in each of these cases the nucleotide change occurred at position c.7007 (the final nucleotide of the exon, which is part of consensus donor splice site (PMID: 17576681, 9536098)). Therefore, the importance of the arginine residue, and of the nucleotide at position c.7006, is unclear at this time. 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.
Integrated Genetics/Laboratory Corporation of America RCV000855635 SCV000695020 uncertain significance not specified 2019-09-09 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7006C>T (p.Arg2336Cys) 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 is also alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 248120 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7006C>T has been reported in the literature in individuals with a personal and/or family history of Hereditary Breast and Ovarian Cancer (Levanat 2012, Alemar 2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported at our laboratory (BRCA1 c.5324T>G , p.Met1775Arg), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (uncertain significance, n=2; likely benign, n=1). One of these submitters reported a co-occurrence with another pathogenic BRCA2 variant (variant not specified) suggesting that this c.7006C>T variant was not the primary cause of disease. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharing Clinical Reports Project (SCRP) RCV000082966 SCV000115040 uncertain significance Breast-ovarian cancer, familial 2 2011-10-18 no assertion criteria provided clinical testing

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