ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7871A>G (p.Tyr2624Cys) (rs431825358)

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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 RCV000216510 SCV000273241 uncertain significance Hereditary cancer-predisposing syndrome 2015-01-07 criteria provided, single submitter clinical testing
Color RCV000216510 SCV000689073 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-18 criteria provided, single submitter clinical testing
GeneDx RCV000657061 SCV000567963 uncertain significance not provided 2017-11-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7871A>G at the cDNA level, p.Tyr2624Cys (Y2624C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). Using alternate nomenclature, this variant has been previously published as BRCA2 8099A>G. This variant was observed in at least two individuals with breast cancer (Infante 2006, Wong-Brown 2015). BRCA2 Tyr2624Cys was not observed in large population cohorts (Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr2624Cys is located within the DNA binding domain (Yang 2002). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Tyr2624Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000479795 SCV000918862 uncertain significance not specified 2018-03-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7871A>G (p.Tyr2624Cys) results in a non-conservative amino acid change located in the helical domain (IPR015252), that binds the DSS1 (deleted in split-hand/split foot syndrome) protein. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 121342 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7871A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Infante 2006, Wong-Brown 2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000257979 SCV000759256 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 2624 of the BRCA2 protein (p.Tyr2624Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs431825358, ExAC 0.001%). This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 16758124). ClinVar contains an entry for this variant (Variation ID: 96860). Experimental studies have shown that this missense change reduces homology-directed repair (HDR) activity of the BRCA2 protein (PMID: 29884841). 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 RCV000479795 SCV000600770 uncertain significance not specified 2017-05-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657061 SCV000887927 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082981 SCV000115055 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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