ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9104A>G (p.Tyr3035Cys) (rs80359165)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203635 SCV000073731 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 3035 of the BRCA2 protein (p.Tyr3035Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs80359165, ExAC 0.04%). This variant has been reported in individuals affected with breast cancer (PMID: 18627636, 19043619, 21520273, 26183948, 20104584, 29681614). ClinVar contains an entry for this variant (Variation ID: 52751). Experimental studies have shown that this missense change does not affect homology-directed DNA repair activity in vitro (PMID: 29394989). 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.
GeneDx RCV000759682 SCV000210495 uncertain significance not provided 2017-02-09 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9104A>G at the cDNA level, p.Tyr3035Cys (Y3035C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). Although this variant, also known as BRCA2 9332A>G, has been observed in multiple individuals with breast cancer, it has also been observed in healthy control populations (Thirthagiri 2008, Borg 2010, Capanu 2011, Dodova 2015). BRCA2 Tyr3035Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr3035Cys occurs at a position that is conserved in mammals and is located in the DNA binding domain (Yang 2002). 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 Tyr3035Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000222955 SCV000275444 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045718 SCV000592257 uncertain significance not specified 2013-06-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759682 SCV000889170 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing
Color RCV000222955 SCV000906958 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045718 SCV000918920 uncertain significance not specified 2019-08-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9104A>G (p.Tyr3035Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 280240 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.00022 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9104A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Gorringe_2008, Thirthagiri_2008, Borg_2010, Hondow_2011, Lai_2017, Wen_2017, Apessos_2018, Liang_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal homology-directed repair (HDR) activity (Guidugli_2018). Five ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000114048 SCV000147539 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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