ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5741G>C (p.Ser1914Thr) (rs80358801)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044740 SCV000072753 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 1914 of the BRCA2 protein (p.Ser1914Thr). The serine residue is weakly conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs80358801, ExAC 0.01%). This variant has been reported in an individual affected with breast/ovarian cancer (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 51925). 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. 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 RCV000217425 SCV000276447 likely benign Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000214177 SCV000279752 uncertain significance not provided 2019-01-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5741G>C at the cDNA level, p.Ser1914Thr (S1914T) at the protein level, and results in the change of a Serine to a Threonine (AGC>ACC). Using alternate nomenclature, this variant would be defined as BRCA2 5969G>C. This variant was observed in 1/1,153 patients undergoing BRCA1/2 testing for a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier 2011). BRCA2 Ser1914Thr was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Threonine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ser1914Thr occurs at a position that is not conserved and is located in the RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Ser1914Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000217425 SCV000903959 likely benign Hereditary cancer-predisposing syndrome 2017-02-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000852 SCV001157926 uncertain significance not specified 2018-10-09 criteria provided, single submitter clinical testing The BRCA2 c.5741G>C; p.Ser1914Thr variant (rs80358801), is reported in the literature in at least one individual affected with breast cancer (Caux-Moncoutier 2011). This variant is reported in ClinVar (Variation ID: 51925), and is found in the African population with an allele frequency of 0.02% (3/15,290 alleles) in the Genome Aggregation Database. The asparagine at codon 1835 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.Ser1914Thr variant is uncertain at this time. References: Caux-Moncoutier V et al. EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. Hum Mutat. 2011 Mar;32(3):325-34.
Integrated Genetics/Laboratory Corporation of America RCV001000852 SCV001361908 uncertain significance not specified 2019-04-29 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5741G>C (p.Ser1914Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250926 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5741G>C has been reported in the literature in individual(s) with personal and/or family history of Hereditary Breast and Ovarian Cancer (Caux-Moncoutier_2011). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.4945_4947delinsTTTT, p.Arg1649SerfsX30; UMD), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x) and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113474 SCV000146685 uncertain significance Breast-ovarian cancer, familial 2 2004-11-25 no assertion criteria provided clinical testing

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