ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.136C>T (p.Pro46Ser) (rs80358425)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164910 SCV000215598 likely benign Hereditary cancer-predisposing syndrome 2017-02-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown)
GeneDx RCV000588395 SCV000617114 uncertain significance not provided 2017-03-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.136C>T at the cDNA level, p.Pro46Ser (P46S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). Using alternate nomenclature, this variant would be defined as BRCA2 364C>T. This variant has been observed in at least one breast cancer family (Olopade 2003). BRCA2 Pro46Ser was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Pro46Ser occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Pro46Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588395 SCV000694534 uncertain significance not provided 2016-11-14 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.136C>T (p.Pro46Ser) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/120990, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of1/1333. The variant of interest has been reported in affected individuals via publications, although with limited information (ie, lack of co-occurrence and cosegregation data). In addition, multiple reputable databases/clinical diagnostic laboratories have cited the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Counsyl RCV000113176 SCV000785758 uncertain significance Breast-ovarian cancer, familial 2 2017-11-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588395 SCV000888976 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing
Color RCV000164910 SCV000906751 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113176 SCV000146231 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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