ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.107C>T (p.Ser36Phe) (rs730881554)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000510014 SCV000608134 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-31 criteria provided, single submitter clinical testing
Color RCV000510014 SCV000903812 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing
GeneDx RCV000590054 SCV000210420 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.107C>T at the cDNA level, p.Ser36Phe (S36F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 335C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser36Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser36Phe occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located within the PALB2 binding domain (Roy 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Ser36Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590054 SCV000694506 uncertain significance not provided 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.107C>T (p.Ser36Phe) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant (Mutation Taster not captured due to low reliability index). This variant was found in 2/120576 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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