ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.742G>A (p.Ala248Thr)

gnomAD frequency: 0.00014  dbSNP: rs55854959
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001087231 SCV000073222 benign Hereditary breast ovarian cancer syndrome 2021-12-18 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 Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
CSER _CC_NCGL, University of Washington RCV000148438 SCV000190137 uncertain significance Breast neoplasm 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 2022-08-01 criteria provided, single submitter clinical testing Observed in individuals with breast cancer, but also in unaffected controls (Olopade et al., 2003; Fackenthal et al., 2005; Haffty et al., 2006; Maxwell et al., 2015; Momozawa et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 970G>A; This variant is associated with the following publications: (PMID: 15744044, 12491487, 26773734, 28814288, 30287823, 15983021, 22034289, 24728327, 27300552, 25637381, 25503501, 11030417, 24504028, 33471991, 33233347)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120387 SCV000600748 uncertain significance not specified 2016-12-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120387 SCV000695062 likely benign not specified 2022-01-10 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 2.3e-05 in 298566 control chromosomes (gnomAD, Bodian_2014, Fackenthal_2005, Momozawa_2018), predominantly at a frequency of 0.00031 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 (example: Gao_2000, Haffty_2006, Maxwell_2015, Dorling_2021), however, it was also found in healthy controls (example: Bodian_2014, Momozawa_2018, Dorling_2021, FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. This variant was found co-occurring with another pathogenic BRCA2 variant via internal testing (BRCA2 c.5164_5165delAG, p.Ser1722fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000586272 SCV000805761 uncertain significance not provided 2017-07-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health 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, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000114118 SCV001482843 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2020-01-08 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798238 SCV002043454 uncertain significance Breast and/or ovarian cancer 2020-11-02 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000120387 SCV002066884 uncertain significance not specified 2021-12-20 criteria provided, single submitter clinical testing This sequence change has been previously described in individuals with breast cancer and reportedly unaffected individuals (PMIDs: 15744044, 12491487, 30287823, 15983021, 22034289, 24728327). This sequence change has been described in the gnomAD database with a frequency of 0.028% in the African subpopulation (dbSNP rs55854959). The p.Ala248Thr change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Ala248Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Ala248Thr change remains unknown at this time.
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, susceptibility to, 2 1997-11-13 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355487 SCV001550390 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The BRCA2 p.Ala248Thr variant was identified in 5 of 14324 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer and was identified in 1 of 1510 chromosomes from healthy individuals (Amendola 2015, Fackenthal 2005, Fackenthal 2012, Haffty 2005). The variant was also identified in dbSNP (ID: rs55854959) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae; as uncertain significance by Ambry Genetics, GeneDx, BIC and three other clinical laboratories), Cosmic (2x), MutDB, LOVD 3.0 (2x), UMD-LSDB (3x as unclassified variant), and BIC (4x as unknown significance). The variant was not identified in the COGR, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 9 of 276698 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 8 of 23984 chromosomes (freq: 0.0003) and European in 1 of 126390 chromosomes (freq: 0.000008), but not in the “Other”, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala248 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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