ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7051G>A (p.Ala2351Thr) (rs80358930)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130893 SCV000185802 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113696 SCV000147007 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000130893 SCV000910879 likely benign Hereditary cancer-predisposing syndrome 2017-02-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212257 SCV000592094 uncertain significance not specified 2015-04-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515244 SCV000611376 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3; Tracheoesophageal fistula 2017-05-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765134 SCV000896360 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000656801 SCV000210414 uncertain significance not provided 2017-10-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7051G>A at the cDNA level, p.Ala2351Thr (A2351T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). Using alternate nomenclature, this variant would be defined as BRCA2 7279G>A. This variant has been reported in at least one individual with early onset breast cancer and one individual with ovarian cancer (Lee 2008, Akbari 2011). BRCA2 Ala2351Thr was observed at an allele frequency of 0.02% (6/30654) in individuals of South Asian ancestry in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala2351Thr occurs at a position that is not conserved and is located within the FANCD2 binding domain (Uniprot). 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 Ala2351Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000045128 SCV000073141 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 2351 of the BRCA2 protein (p.Ala2351Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs80358930, ExAC 0.02%). This variant has been reported in individuals affected with breast and ovarian cancers (PMID: 18284688, 21965345). However, it was reported to co-occur with a pathogenic allele in the BRCA1 gene in one individual in the Breast Cancer Information Core database (PMID: 10923033), which suggests that this c.7051G>A substitution in BRCA2 was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 52256). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The threonine 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 and their clinical significance is uncertain. 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 RCV000212257 SCV000600732 uncertain significance not specified 2017-03-06 criteria provided, single submitter clinical testing

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