ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7021C>T (p.Arg2341Cys) (rs41293505)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130453 SCV000185317 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000130453 SCV000906543 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing
Counsyl RCV000076986 SCV000785845 uncertain significance Breast-ovarian cancer, familial 2 2017-12-27 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735598 SCV000863736 likely benign Breast and/or ovarian cancer 2012-05-10 no assertion criteria provided clinical testing
GeneDx RCV000160126 SCV000210413 uncertain significance not provided 2017-11-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7021C>T at the cDNA level, p.Arg2341Cys (R2341C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 7249C>T. This variant has been observed in at least two individuals with breast cancer and one with pancreatic cancer (Warren 2011, Wong-Brown 2015, Zhen 2015). BRCA2 Arg2341Cys was not observed at a significant frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Arg2341Cys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Arg2341Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781128 SCV000918977 uncertain significance not specified 2018-07-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7021C>T (p.Arg2341Cys) results in a non-conservative amino acid change located to the linker region in the encoded protein sequence, a region whose functional significance is unknown (Warren 2011). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 246036 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7021C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Warren 2011, Wong-Brown 2015) and was found also in one patient with pancreatic cancer (Zhen 2014). These reports however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (in UMD: BRCA1 c.3048_3067del (p.Asn1018HisfsX3) and BRCA2 c.3744_3747delTGAG (p.Ser1248ArgfsX10)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) ctie the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000227614 SCV000283307 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2341 of the BRCA2 protein (p.Arg2341Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs41293505, ExAC 0.009%). This variant has been reported in individuals affected with breast and pancreatic cancer (PMID: 21741379, 25682074, 25356972). This variant is also known as 7249C>T. in the literature. ClinVar contains an entry for this variant (Variation ID: 91469). 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. In addition, the cysteine amino acid residue is 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. In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000076986 SCV000108783 uncertain significance Breast-ovarian cancer, familial 2 2008-07-01 no assertion criteria provided clinical testing

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