ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10111A>G (p.Thr3371Ala) (rs80358393)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000034424 SCV000883505 likely benign not provided 2018-04-24 criteria provided, single submitter clinical testing The BRCA2 c.10111A>G; p.Thr3371Ala variant (rs80358393) has been described in individuals affected with breast cancer who also harbor a known pathogenic BRCA1 variant (see link to BIC database). This variant has also been observed in individuals with no personal or family history of cancer (Johnston 2012). It is reported in ClinVar (Variation ID: 37720) and observed in the general population at an overall frequency of 0.0007% (2/277018 alleles) in the Genome Aggregation Database. The threonine at codon 3371 is moderately conserved but computational algorithms (PolyPhen-2, SIFT) predict this variant to be tolerated. Based on available information, this variant is considered likely benign. References: BIC database: Johnston J et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet. 2012 Jul 13;91(1):97-108.
Ambry Genetics RCV000131701 SCV000186738 likely benign Hereditary cancer-predisposing syndrome 2017-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,In silico models in agreement (benign)
Biesecker Lab/Human Development Section,National Institutes of Health RCV000034424 SCV000043240 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000031301 SCV000145754 uncertain significance Breast-ovarian cancer, familial 2 2000-06-12 no assertion criteria provided clinical testing
Color RCV000131701 SCV000902875 benign Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing
Counsyl RCV000031301 SCV000221120 likely benign Breast-ovarian cancer, familial 2 2015-02-05 criteria provided, single submitter literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000167810 SCV000592312 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-05-11 criteria provided, single submitter clinical testing
GeneDx RCV000043714 SCV000210697 likely benign not specified 2017-09-06 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 RCV000034424 SCV000694494 likely benign not provided 2016-08-22 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a medium size and polar Threonine (T) with a small size and hydrophobic Alanine (A). The affected Threonine (aa 3371) is located at the C-terminal end of the 3410 amino acid long protein, outside of the know BRCA2 functional domains. 3/4 in silico tools predict neutral outcome for this change (SNPs&GO was not considered due to low reliability index). The variant is absent from the large and broad cohorts of the ExAC project. It was reported in HBOC spectrum patients however without strong evidence for pathogenicity. Additionally, BIC database lists two patients with co-occurrence with a potentially pathogenic BRCA1 mutations p.Gln1538Ter and p.Leu1260?fs indicating the variant to be in the benign spectrum. One internal sample also carried a pathogenic BRCA1 variant c.5335delC/p.Q1779fs*14, further supporting the benign classification. Furthermore, clinical diagnostic centers classify variant as Likely Benign/Benign (without evidence to independently evaluate). Considering all evidence, the variant is classified as Likely Benign until more information becomes available.
Invitae RCV000167810 SCV000071727 likely benign Hereditary breast and ovarian cancer syndrome 2017-11-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034424 SCV000888970 likely benign not provided 2018-06-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031301 SCV000053906 benign Breast-ovarian cancer, familial 2 2012-02-01 no assertion criteria provided clinical testing

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