ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.742G>A (p.Ala248Thr) (rs55854959)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131381 SCV000186357 likely benign Hereditary cancer-predisposing syndrome 2018-03-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown)
Breast Cancer Information Core (BIC) (BRCA2) RCV000114118 SCV000147649 uncertain significance Breast-ovarian cancer, familial 2 1997-11-13 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148438 SCV000190137 uncertain significance Neoplasm of the breast 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Color RCV000131381 SCV000910963 likely benign Hereditary cancer-predisposing syndrome 2016-03-02 criteria provided, single submitter clinical testing
GeneDx RCV000586272 SCV000210254 uncertain significance not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.742G>A at the cDNA level, p.Ala248Thr (A248T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). BRCA2 Ala248Thr, also known as 970G>A using alternate nomenclature, has been observed in patients with early-onset breast cancer and, in one study, was absent in healthy age-matched controls (Olopade 2003, Fackenthal 2005, Haffty 2006, Maxwell 2014). This variant was also identified in 1/43 healthy African individuals undergoing whole genome sequencing (Bodian 2014); of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BRCA2 Ala248Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ala248Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120387 SCV000084539 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000586272 SCV000695062 uncertain significance not provided 2016-05-03 criteria provided, single submitter clinical testing Variant summary: The c.742G>A (p.Ala248Thr) in BRCA2 gene is a missense variant involves a non-conserved nucleotide and 2/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at a frequency of 0.003% (4/115300 chrs tested), being most prevalent in individuals of African descent (3/9740chrs tested), which does not exceed the maximal expected allele frequency for a non-common pathogenic BRCA2 variant (0.00075). The variant was identified in several affected individuals without strong evidence of causality and BIC reports a co-occurrence with a known pathogenic mutation, c.66_67delAG in one of the individuals. The variant of interest has been reported as VUS/Likely Benign/Polymorphism by reputable databases/clinical laboratories and published reports. Taken all together, the variant was classified as VUS-Possibly Benign.
Invitae RCV000195334 SCV000073222 likely benign Hereditary breast and ovarian cancer syndrome 2017-11-18 criteria provided, single submitter clinical testing
PreventionGenetics RCV000586272 SCV000805761 uncertain significance not provided 2017-07-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120387 SCV000600748 uncertain significance not specified 2016-12-15 criteria provided, single submitter clinical testing

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