ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10045A>G (p.Thr3349Ala) (rs80358387)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163020 SCV000213508 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031300 SCV000145744 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148421 SCV000190120 likely benign Neoplasm of the breast 2014-06-01 no assertion criteria provided research
Color RCV000163020 SCV000683390 likely benign Hereditary cancer-predisposing syndrome 2015-06-08 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031300 SCV000244416 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000000919
GeneDx RCV000043705 SCV000210695 likely benign not specified 2017-12-28 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.
Integrated Genetics/Laboratory Corporation of America RCV000043705 SCV000694490 likely benign not specified 2017-04-24 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.10045A>G (p.Thr3349Ala) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that does not lie within a known functional domain (InterPro) at the extreme C-terminal end of the protein. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database gnomAD in 29 of 277070 control chromosomes from all ethnicities, but was predominantly observed in the Latino subpopulation at a frequency of 0.000553 (19/34376). This frequency is slightly less than the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), providing some evidence that this may be a benign polymorphism found primarily in the populations of Latino origin. The variant has been reported in the literature in HBOC patients and families, without strong evidence for causality (lack of co-segregation and co-occurrence data) and has also been found in controls. In addition, one patient with the variant showed retention of the wild-type allele and loss of the allele harbouring the variant, suggesting the variant is not deleterious (Osorio_BRCA1&2_Int J Cancer_2002). Multifactorial models which incorporate family history, co-segregation, co-occurrence, and tumor pathology has predicted the variant to be likely neutral (Easton_2007, Lindor_2012). A functional study showed that the variant does not impact splicing (Houdayer_BRCA1&2_HM_2012). Multiple clinical diagnostic laboratories/reputable databases and literature reports have classified this variant as likely benign or benign. In addition, a polymorphism that truncates the protein upstream of the variant (c.9976A>T; p.Lys3326X) has previously been classified as benign, suggesting the variant of interest likely does not impact protein function. Taken together, this variant is classified as likely benign until more evidence becomes available.
Invitae RCV000195324 SCV000071718 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000043705 SCV000538477 likely benign not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 5/11516 Latino; ClinVar: 4 B/LB, 1 VUS
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759571 SCV000888967 likely benign not provided 2018-05-04 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031300 SCV000053905 benign Breast-ovarian cancer, familial 2 2008-01-08 no assertion criteria provided clinical testing
Vantari Genetics RCV000163020 SCV000267028 likely benign Hereditary cancer-predisposing syndrome 2016-02-04 criteria provided, single submitter clinical testing

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