ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001087231 SCV000073222 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131381 SCV000186357 likely benign Hereditary cancer-predisposing syndrome 2019-04-18 criteria provided, single submitter clinical testing In silico models in agreement (benign);Co-occurence with mutation in same gene (phase unknown)
CSER _CC_NCGL, University of Washington 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
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120387 SCV000600748 uncertain significance not specified 2016-12-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120387 SCV000695062 uncertain significance not specified 2019-08-09 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.742G>A (p.Ala248Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 329898 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.00028 within the African or African-American 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.742G>A has been reported in the literature in individuals affected with breast cancer (Gao_2000, Haffty_2006, Maxwell_2015), however, it was also found in healthy controls (Bodian_2014, Momozawa_2018, and in the FLOSSIES database). 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. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as VUS (3x) or likely benign (3x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics,PreventionGenetics RCV000586272 SCV000805761 uncertain significance not provided 2017-07-05 criteria provided, single submitter clinical testing
Color RCV000131381 SCV000910963 likely benign Hereditary cancer-predisposing syndrome 2016-03-02 criteria provided, single submitter clinical testing
Mendelics RCV000114118 SCV001138978 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000120387 SCV000084539 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000114118 SCV000147649 uncertain significance Breast-ovarian cancer, familial 2 1997-11-13 no assertion criteria provided clinical testing

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