ClinVar Miner

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

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Total submissions: 9
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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 2018-05-11 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175345 SCV000694534 uncertain significance not specified 2019-12-26 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.136C>T (p.Pro46Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251310 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.136C>T has been reported in one African American individual affected with Hereditary Breast and Ovarian Cancer (BIC and Olopade 2003). However the variant was also found in one African American woman, older than age 70 years who have never had cancer (FLOSSIES database). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge no experimental evidence demonstrating its impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
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 Health, Inc RCV000164910 SCV000906751 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 46 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 12491487). This variant has also been identified in 4/282690 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588395 SCV001334479 uncertain significance not provided 2020-03-01 criteria provided, single submitter clinical testing
Invitae RCV001306963 SCV001496354 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-17 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 46 of the BRCA2 protein (p.Pro46Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs80358425, ExAC 0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 12491487). ClinVar contains an entry for this variant (Variation ID: 51111). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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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