ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3910A>G (p.Thr1304Ala) (rs28897723)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044305 SCV000072318 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130607 SCV000185483 likely benign Hereditary cancer-predisposing syndrome 2018-01-04 criteria provided, single submitter clinical testing in silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000417556 SCV000515650 likely benign not specified 2017-12-08 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000031446 SCV000786159 uncertain significance Breast-ovarian cancer, familial 2 2018-03-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130607 SCV000910964 benign Hereditary cancer-predisposing syndrome 2016-02-22 criteria provided, single submitter clinical testing
Mendelics RCV000031446 SCV001139078 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170462 SCV001333042 uncertain significance Breast and/or ovarian cancer 2017-12-29 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031446 SCV000054051 benign Breast-ovarian cancer, familial 2 2009-02-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031446 SCV000146330 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353744 SCV000591881 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Thr1304Ala variant was not identified in the literature in a patient population. The variant was identified in dbSNP (ID: rs28897723 as "With other allele"), ClinVar (1x as benign by SCRP; 3x as likely benign by Ambry Genetics, GeneDx, and Invitae; and 4x as uncertain significance by Counsyl, BI, CHEO Genetics Diagnostic Laboratory, and at Sinai Health System), MutDB, LOVD 3.0 (2x), and UMD-LSDB (8x as unclassified variant). The variant was not identified in Cosmic, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 7 of 205258 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 4492 chromosomes (freq: 0.0002) and European in 6 of 95212 chromosomes (freq: 0.00006); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Thr1304 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 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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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